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The newsletterDrug Development Department (DITEP) at Gustave Roussy

DITEP

Gustave Roussy - November2015

INTERACTIONS Ditep and the GI tract committee

interactionsfocus

congresses & publications

editorial

case reporttrial portfolio

THE DYNAMICS OF DITEP

editorial

SENATORIAL VISIT TO DITEP 14/09/15

DITEP OPEN DAY 14/09/15

THE DAILY LIFE OF GUSTAVE ROUSSY AND, AS A RESULT, THAT OF DITEP IS PUNCTUATED BY MULTIPLE VISITS AND OPPORTUNITIES.

On Monday September 14th 2015, the Senate President Mr Gérard Larcher, honoured us by visiting, along with an enthusiastic senatorial delegation, the hospital, medical and administrative premises of DITEP which has expanded by 1,200 m2 enabling more than 100 different professionals to work together in the same geographic location. This visit underlined the commitment of DITEP to patients suffering from cancer thanks to clinical research which is seen as the provision of care.

This visit of the President of the Senate, accompanied by Senators Alain Milon, Catherine Deroche and Elisabeth Doineau, reporters for the draft law for the modernisation of the healthcare system permitted to underscore the International excellence of the Drug Development Department of Gustave Roussy. The availability of new premises close to the hospital unit and day hospital thus enables professionals to be brought together on the same site which until then had been spread out over a 3 year period over 7 different floors of the hospital.

With a total surface area of close to 1,200 m2 these new premises benefit from an innovative and transparent architecture which enables DITEP team members (that is approximately fifteen specialities) to work together on a daily basis in the service of patients. It is structured around an in-patient and day hospital service, a consultation unit and an early phase operational service responsible for the operational application of all the early phase therapeutic trials undertaken at Gustave Roussy. DITEP furthermore accommodates another translational research laboratory dedicated to

storage and pre-analysis which will enable the molecular, pharmacological and immunological characterisation of tumours (ET-EXTRA module).

On the same day, Monday September 14th, DITEP opened its doors to other specialists from Gustave Roussy to enable them to better understand the diversity of its tasks: clinical research associates, schedulers, research medical assistants, sampling administrators, project leaders, nurses, managers and those in-charge of scientific publications etc. More than 70 individuals belonging to the various departments of Gustave Roussy were thus able to visit DITEP and to exchange posters produced for this occasion with those present.

Finally, DITEP remains committed to ongoing innovation. As such, since August 2015, 4 to 6 ultrasonography-guided tumour biopsies have been undertaken every week in the Day Hospital of DITEP by radiologists from the Interventional Radiology Unit thanks to the support of nurses and doctors from DITEP. This achievement would not have taken place without the support of Prof. De Baere, his team, Dr Antoine Hollebecque, the Head of the SITEP Out-Patient Unit, and the SITEP healthcare managers (Mrs Sandrina Rodrigues and Mrs Dielenseger). This deployment, enables us to shorten the waiting time of our patients in order to gain access to a molecular and immunological profile of their tumour.

Pr Jean-Charles SORIA

publications

NEW PUBLICATIONS BY DITEP PHYSICIANS ON PHASE 1 TRIALS I: JULY-OCTOBER 2015Gupta S, Argiles G, Munster PN, Hollebecque A, Dajani O, Cheng J, Wang R, Swift A, Tosolini A, Piha-Paul SA (2015) A Phase I Trial of Combined Ridaforolimus and MK-2206 in Patients With Advanced Malignancies. Clin Cancer Res [Epub ahead of print].

Helissey C, Biondani P, Roquet F, Lanoy E, Mir O, Varga A, Massard C, Gazzah A, Ribrag V, Bahleda R, Postel-Vinay S, Angevin E, Deutsch E, Soria JC, Hollebecque A (2015) Patients aged over 75 years enrolled in phase I clinical trials: The gustave roussy experience. Int J Cancer [Epub ahead of print].

Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay J-Y, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz R-D, Hidalgo M, Chan E, Schuler M, Lasserre SF, Makrutzki M, Sirzen F, Veronese ML, Tabernero J, Baselga J (2015) Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med 373:726-736.

Massard C, Penttinen HM, Vjaters E, Bono P, Lietuvietis V, Tammela TL, Vuorela A, Nykanen P, Pohjanjousi P, Snapir A, Fizazi K (2015) Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: An Open-label Phase 1 Study. Eur Urol [Epub ahead of print].

Piha-Paul SA, Munster PN, Hollebecque A, Argiles G, Dajani O, Cheng JD, Wang R, Swift A, Tosolini A, Gupta S (2015) Results of a phase 1 trial combining ridaforolimus and MK-0752 in patients with advanced solid tumours. Eur J Cancer 51:1865-1873.

Tabernero J, Bahleda R, Dienstmann R, Infante JR, Mita A, Italiano A, Calvo E, Moreno V, Adamo B, Gazzah A, Zhong B, Platero SJ, Smit JW, Stuyckens K, Chatterjee-Kishore M, Rodon J, Peddareddigari V, Luo FR, Soria J-C (2015) Phase I Dose-Escalation Study of JNJ-42756493, an Oral Pan–Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors. J Clin Oncol [Epub ahead of print].

NEW PUBLICATIONSJULY-OCTOBER 2015

A NEW 2015 SEMESTER MARKED BY THE DESIRE OF DITEP TO SHARE THE RESULTS OF THE EARLY TRIALS CARRIED OUT WITHIN THE DEPARTMENT WITH THE INTERNATIONAL SCIENTIFIC COMMUNITY: REVIEW OF THE HIGHLIGHTS OF DITEP ACTIVITY AT THE WCLC, ECC AND AACR-NCI-EORTC CONGRESSES.

WCLC 2015 (WORLD CONFERENCE ON LUNG CANCER, DENVER, 6-9 SEPTEMBRE 2015)Unmissable meeting point for lung cancer and other thoracic tumour specialists, the WCLC attracts more than 7,000 experts from over 100 countries. Dr Benjamin Besse presented the encouraging results of the trial carried out with lucitanib (tyrosine kinase inhibitor targeting VEGFR-FGFR-PDGFR) in a cohort of patients suffering from advanced thymic epithelial tumours. Dr David Planchard undertook an assessment of 4 year’s activity of the « Molecular Tumor Board » at Gustave Roussy, in the field of personalised medicine. Present on this board, DITEP physicians are actively involved in the identification and treatment of patients suffering from lung cancer thanks to therapies targeting molecular abnormalities and immunotherapies.

ECC 2015 (EUROPEAN CANCER CONGRESS, VIENNE, 25-29 SEPTEMBRE 2015)The results of seven phase 1 trials undertaken at DITEP were the subject of oral presentations including two carried out by doctors from the department on the occasion of the new edition of the European Congress dedicated to cancer. Dr Andrea Varga and Prof. Jean-Charles Soria respectively gave the results of the efficacy of rociletinib (tyrosine kinase inhibitor specifically targeting mutant forms of EGFR), and the latest results on pembrolizumab (anti-PDL1). During a session devoted to early trials and presided over by Prof. Jean-Charles Soria, the results were presented

of a trial evaluating S49076 (an inhibitor of the MET tyrosine kinase receptor) in advanced solid tumours, E7438 (histone methyl-transferase inhibitor EZH2), the combination of SAR405838 (HDM2 inhibitor) and pimasertib (MEK inhibitor) in advanced solid tumours and vanucizumab, a bispecific anti-ANG-2/anti-VEGF-A antibody. Dr Aurélien Marabelle moreover shared his expertise in immunotherapy as an invited speaker and chair in three sessions of the scientific programme and of a symposium organised by Amgen on this subject.

AACR-NCI-EORTC (INTERNATIONAL CONFERENCE ON MOLECULAR TARGETS AND CANCER THERAPEUTICS, BOSTON, 5-9 NOVEMBRE 2015) This International meeting devoted to new anticancer therapies included Prof. Jean-Charles Soria among the presidents of its Scientific Committee. Two posters on studies carried out at DITEP will be presented: the GEFTREM study by Dr David Planchard, and the INPAKT study by Dr Eric Angevin. The first evaluates the combination of tremelimumab and gefitinib in patients with a non-small-cell cell lung cancer with EGFR mutation. The second, a Gustave Roussy sponsored trial supported by the National Cancer Institute (INCA) and the caritative ARC Foundation in the context of the CLIP2, network of labelled french early phase centers explores the safety, tolerance and efficacy of LY2780301 (p70/Akt inhibitor) in combination with gemcitabine in advanced or metastatic cancers.

DITEP, ATTENDANCE AT MAJOR INTERNATIONAL CANCER EVENTS

congressesDr Anas GAZZAH Nelly HAINAULT

focus

EXCHANGES BETWEEN DITEPAND THE GASTROINTESTINAL TRACT COMMITTEE

A CLOSE COLLABORATION BETWEEN DITEP AND THE GI CANCERS COMMITTEE ENABLES PHASE 1 TRIALS FOCUSSED ON DIGESTIVE TRACT TUMOURS TO BE CARRIED OUT AND TO DIRECT MORE OF OUR PATIENTS TOWARDS NEW COMPOUNDS ON THE BASIS OF GENOMIC ABNORMALITIES.

TRIALS FOCUSSED ON DIGESTIVE TRACT TUMOURS

BRAF MUTATED CANCER OF THE COLON The mutation of the BRAF gene occurs in approximately 8% of cancers of the colon and is a poor prognostic factor. The MEK116833 trial, offers these BRAF mutated patients a novel triple combination of Dabrafenib, Trametinib and Panitumumab. Eight patients have been given this combination since the beginning of 2015 with very encouraging results. The GO28885 trial is another trial targeting this population. It proposes an anti-ERK in patients having received less than 4 lines of treatment. Here, once more, due to the promising results, a new extension cohort has just been reopened.

IDH MUTATED CHOLANGIOCARCINOMA IDH gene mutations represent close to 20% of the intrahepatic cholangiocarcinomas. The AG120-002 trial enables these patients to be treated with an IDH-1 inhibitor. These treatments have already shown signs of activity and excellent tolerance, notably in acute myeloblastic leukaemia.

STOMACH CANCER AND HEPATOCELLULAR CARCINOMAThe I7W-MC-JQBA trial testing a new anti-angiopoietin 2 has just started. After a dose escalation phase with monotherapy, this treatment will then be combined with Ramucirumab (anti-VEGFR2) and will explore the efficacy of this combination in cancers of the stomach and hepatocellular carcinomas.

CANCER OF THE STOMACH POSITIVE FOR EBVStomach cancers linked to EBV represent approximately 8% of stomach cancers. For these patients, it is possible to propose Nivolumab (anti-PD1) in the context of the CA209-358 trial.

IN THE PIPELINEThe KEYNOTE-158 trial will include 2 cohorts for digestive tract tumours (cholangiocar-cinoma and epidermoid carcinoma of the anal canal) enabling Pembrolizumab (anti-PD1) to be proposed, the CA212-115 trial (combination of Nivolumab with an anti-CXCR4) for pancreatic cancers, the CC90003ST001 trial (anti-ERK) notably for BRAF mutated colon cancers.

interactions

Dr Antoine Hollebecque

MUTATIONS OF THE IDH1 AND IDH2 GENES HAVE BEEN DEMONSTRATED THANKS TO HIGH FLOW THROUGHPUT SEQUENCING. THEY HAVE BEEN FOUND IN LOW GRADE GLIOMAS AND IN SECONDARY GLIOBLASTOMAS AND THEN IN AMLS.

The functional consequences of the presence of these mutations constitute a model for oncogenesis in which the accumulation of a metabolite, 2-HG, interferes with the regulation of intracellular metabolism and epigenesis. Heterozygote mutations of IDH1 and IDH2 modify the activity of enzymes which they code for. This induces the neomorphic production of an oncometabolite D-2HG. D-2HG appears to play a key role in the oncogenesis process and acts as a competitive inhibitor of α-KG, an essential co-factor for the activity of oxygenases. These regulate the varied biological processes including the hypoxia response, angiogenesis, the maturation of collagens, the extracellular matrix and the control of gene expression through epigenetic mechanisms. This excess of D-2HG induces a hypermethylation of DNA and of histones which inhibit the expression of key genes for cellular differentiation and by inducing a differentiation blockade with a phenotype of immature cells irrespective of the nature of the tissue.

INHIBITORS OF MUTATED FORMS OF IDH1 AND IDH2The proof of concept for the potential efficacy of an inhibitor of mutated forms of IDH1 R132 and IDH2 (R140Q and R172K) has been achieved

in parallel in gliomas for IDH1 and in AML for IDH2.

On AML blast cells with IDH2 (R140Q or R172K) mutations, the level of 2HG is normalized and a final differentiation of blast cells into polynuclear neutrophils is observed. The differentiating effect is shown by the fact that these differentiated cells contain the R140Q mutation of IDH2. The AML blast cells without an R140Q mutation of IDH2 are not sensitive to the effect of the inhibitor.

These new inhibitors are currently undergoing phase 1 studies and promising results have been reported in myeloid haemopathies in which the clinical results are in agreement with the preclinical ones (NCT01915498, NCT02074839). Gustave Roussy have tested the AG221 inhibitor of mutant IDH2; the AG120 inhibitor of mutant IDH1 and the AG 881 inhibitor of mutant IHD1 and mutant IDH2.

• DiNardo C, Stein EM, Altman JK et al. AG-221, an oral, selective, first-in-class, potent inhibitor of the IDH2 mutant enzyme, induced durable responses in a phase I study of IDH2 mutation-positive advanced hematologic malignancies European Hematology Association Learning Center Jun 13,2015; 100710: Abstract P569.

• de Botton S, Pollyea DA, Stein EM et al. Clinical safety and activity of AG-120, a first-in-class, potent inhibitor of the IDH1 mutant protein, in a phase 1 study of patients with advanced, IDH1-mutant hematological malignancies. European Hematology Association Learning Center Jun 13, 2015; 100704: Abstract P563.

focus

IDH INHIBITORS

Dr Stéphane de BOTTON

Multiple myeloma is a common illness over the age of 60 years (annual incidence: 60/100,000 in the elderly), but for which no molecular personalised medical approach is currently used. Mr P. 66 years of age, has been suffering from an IgA Lambda multiple myeloma for the last 5 years. Prior to this he had received the following treatments: Bortezomib + Melphalan + Dexamethasone followed by an autograft with Melphalan; Lenalidomide + Prednisolone; Bortezomib + Cyclophosphamide + Dexamethasone.

During the last relapse, Mr P was tired and had lost 3 kg. A BRAF screening was undertaken by enrichment and plasmocytic cell sorting, a technique refined by the cytology team at Gustave Roussy (Drs V Verge, N Auger, S Cotteret and L Lacroix). A BRAF mutation V600E was identified, which enabled the patient to be proposed a targeted treatment (BRAF and MEK inhibitor combination)

Treatment was well tolerated and continued without interruption. The tiredness

disappeared in 2 weeks and the patient regained his body weight in one month. The serum monoclonal component plummeted – testimony to a rapid anti-tumour activity. At the time of writing, the serum monoclonal component had fallen by more than 95%. The response kinetics obtained appear to be at least as rapid as the previous chemotherapy received (Figure 1).

Though the BRAF mutation is only found in 10% of patients with multiple myeloma, identifying it enables patients to directly benefit from a targeted treatment. This approach illustrate the development of personalised molecular medicine in multiple myeloma..

CLINICAL CASE

case report

Dr Jean-Marie MICHOT

WEB SPEAKS OF DITEP!

news

A number of articles have been published on the sites of various senators following the visit of the Senat President, Mr Gérard Larcher. An editorial also appeared on: 94.citoyens.com.

You can find the Press Release on this visit at our site.

DITEP & ISO 9001

DITEP IS TAKING STEPS TOWARDS THE ISO 9001V2015 CERTIFICATION NORM:ISO 9001V2015.

A personnel awareness meeting was held on the 22/09/2015 with a greater than 50% level of participation.

The first management review took place on the 12/10/2015 in order to validate several actions including the nomination of process pilots and the setting up of working groups for the des-cription of the process.

Thank you for the involvement of all the contri-butors as certification is a project for one and all of us!

www.gustaveroussy.fr/fr/gerard-larcher-a-la-rencontre-du-ditep

www.gustaveroussy.fr/sites/default/files/gustaveroussy_visite_senat_au_ditep.pdf

COMPOUND PROTOCOL SPONSOR TARGETABBV-399 M14-237 Abbvie c-Met inhibitor

Adalimumab TAM-RT Gustave Roussy Tumor Necrosis Factor α (TNFa) inhibitor

AG120 AG120-C-002solid tumors Agios IDH1 inhibitor

AG120 AG120-C-001 Hem Agios IDH1 inhibitor

AG221 AG221 - C - 001 Hem Agios IDH2 inhibitor

AG221 AG221 - C – 003solid tumors Agios IDH2 inhibitor

AG 881 AG-881-C-001 AGios IDH1/IDH2 inhibitor

AMG 228 AMG228-20140131 Amgen GITR agonistic Ab

AMG 232 AMG232 FIH_CSET 2013-2094 Amgen MDM2 inhibitor

APLIDINE +Bortezomib APL-A-012-13 Pharmamar RAC1 & JNK activation

ARGX-110 ARGX-110 -1201 ArGEN- X monoclonal IgG1 Ab target CD70

BAY 1125976 BAY AKT 16647 Bayer oral allosteric AKT1 inhibitor

BAY 1238097 Bay 17437 Bayer Bet inhibitor

BGJ 398 CBGJ398X2101 Novartis FGF-R 1, 2, 3 inhibitor

BIBW2992 Docetaxel+cisplatine GORTEC 2013-01 TAPIS Gortec Irreversible EGFR (HER1) and

HER2 inhibitor

BYL719 CBYL719Z2102 Novartis PI3K inhibitor

CC-122 CC-122-ST-001CC-122-NHL-001 Celgene Pleiotropic Pathway Modifier

(PPM)

CLR457 CCLR457X2101 Novartis PI3K Inhibitor

Crizotinib Acsé Unicancer RTK (ALK et MET)inhibitor

DEBIO 11-43 DEBIO 1143-201 Debiopharm protein apoptosis blockage

E7438 E7438-G000-101 Eisai histone methyl transferase EZH2 inhibitor

EGF816 + INC280 CINC280X2105C Novartis cMET+EGFR inhibitor

GDC-0032 GO00886 (PMT4979g) Genentech High selective PI3K inhibitor

GDC-0575 GP28153 Genentech Chk1 inhibitor

GDC-0994 GO28885 Genentech ERK inhibitor

GDC-0994 + cometinib GO29653 Genentech MEK + ERK Inhibitor

GSK1120212 *(Trametinib)

MEK116833FAK114746 TRAM GlaxoSmithKline

Highly selective inhibitor of MEK1/MEK2 activation and

kinase activity

GSK2879552 200858 SCL LSD1 GSK High selective LSD1 inhibitor

INC280 +EGF816 CINC280X2105C Novartis EGF, T790M, C-MET

Ipilimumab MEL-IPI-RX Gustave Roussy anti-CTLA4 monoclonal antibody

JNJ-42756493 42756493EDI1001 J&J Pan FGFR: 1, 2, 3, 4 Inhibitor

LTX-315 C12-315-03 Lytix Biopharma Immunostimulant lytic-peptid

LY3009120 I6x-MC-JBDA Lilly pan-RAF inhibitor

LY3039478 I6F-MC-JJCA Lillypotently inhibits Notch cleavage

and downstream Notch signaling

LY3127804+ ramucirumab 17W-MC-JQBA Lilly Ang 2

MAG-Tn3 + AS15 Matrivaccin Pasteur active immunization therapy

trial portfolio

MEDI4736 MedImmune 4736-1108 MedImmune Immunoglobulin G1kappa anti PD-L1

MEN 1112 ARMY-1 Menarini CD157 antigen

MLN2480 C 28002 Millenium pan RAF/mTOR/Aurora A kinase

MPDL3280A PCD4989g Genentech Humanized mAb isotype IgG4/kappa against PD-L1

MPDL328 +Erlotinib WP29158 Genentech

Humanized mAb isotype IgG4/kappa against PD-L1

EGFR inhibitor

MPDL328 +RO7009789 PB29392 Genentech Humanized mAb isotype IgG4/

kappa against PD-L1

MPDL328 +RO5509554 PB29428 Genentech

Humanized mAb isotype IgG4/kappa against PD-L1

Humanized mAb IgG1 CSF1R inhibitor

NBTXR3 NBTXR3-103 Nanobiotix Radiotherapy + nanoparticles

Necitumumab I4x-MC-JFCQ Lilly EGFR & CDK 4/6 inh

Necitumumab + pembrolizu-mab I4x-MC-JFCQ Lilly EGFR /CDK4/6 & Anti PD1

Nivolumab CA 209-358 (EBV+ HPV+) BMS Humanized Mab IgG4 target

CD137

Nivolumab + Urelumab CA 186-107 BMS Humanized Mab IgG4 target CD137 + Anti PD1

ODM 203 KIDES Orion FGFR1-4 and VEGFR1-3 inhibitor

ORY-1001 L01-ORY-1001 Oryzon Genomics LSD1/KDM1A inhibitors

OTX015 OTX015_108 Oncoethix BET Inhibitor

PanitumumabDabrafenib Trametinib

MEK116833 GlaxoSmithKline

human immunoglobulin G2 (IgG2) monoclonal antibody

directed against human EGFRMEK &ERK phosphorylation

inhibition

PCA062 CPCA062X2101 Novartis p Cad

PDR001 CPDR001X2101 Novartis PD1

PIM447 + ruxolitinib (INC424) + LEE011 CPIM447X2104C Novartis JAK 1 &2 / Pan PIM kinase/

CDK4/6 inhibitor

PMT4979g GO00886 Genentech PI3K

RO6895882 BP28920 Roche Immunocytokine –Interleukin 2 variation

S55746 CL1-55746-001 Servier BCL2 inhibitor

S78454 CL1-78454-003 Servier hydroxymate-based pan-HDAC inhibitor

SAR 125844 TED11449 Sanofi MET tyrosine kinase inhibitor

SAR408701 TED 13751 Sanofi CEA CAM5

SAR428926 TED 14147 Sanofi anti LAMP1/linker SPDB

TAS 114 + S1 TPU-TAS-114-102 Taiho Thymidine synthethase inhibitor

TAS 120 TAS-120-101 Taiho Irreversible FGFR inhibitor

Urelumab BMS-663513 CA186-011 BMS Humanized Mab IgG4 target

CD137