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NewsletterFrom the Gustave Roussy Drug Development Department

(Drug Development Department)

Gustave Roussy - November 2016

INTERACTIONS The Drug Development Departmentand the Pediatric Committee

interactionsfocus

congress edito

newstrials portfolio

DITEP

with its identity firmly established, ditep continues to develop and sponsor clinical research which is conceived as a component of patient care and is based on the principle of access by the greatest number of patients to therapeutic advances and early trials.

DITEP has become a key entity which wishes to bring the issues raised by clinical research to the national stage. Access to advances depends on the complex and fragile ecosystem of clinical research in France. In this context, DITEP is pleased to announce that a round-table will be held on 9th December 2016 at the Marriott Rive Gauche, Paris, on the theme of “issues and progress in the early development of therapies in oncology”. We are delighted to be in a position to welcome the participation of key actors in the field of innovation in cancer therapy: the ANSM, DGOS, INCA and HAS. The importance of this colloquium is reflected by the fact that the most senior representatives of these institutions will be attending: Dr. Alexandre Moreau of the ANSM, Madame Anne-Marie Armantéras-de-Saxcé of the DGOS, Professor Norbert Ifrah from INCA and Professor Agnès Buzin from the HAS. Participating with them will be 3 leading pioneers of early trials in France: Professor Jean-Yves Blay (Director of the Léon Bérard CLCC in Lyon), Profes-sor Antoine Italiano from Bordeaux and Professor Christophe Le Tourneau from the Institut Curie. Our collaborators in the pharmaceutical industry will be represented both at the corporate level and by their national directors. To highlight the debate, three world experts in early trials will bring an international pers-pective: Professor Emile Voest (Director of the NKI, Amsterdam), Dr. Anthony Tolcher (START, San Antonio)

DITEP’S DYNAMIC

editorial

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Drug Development DepartmentDITEP

DITEP 2016Paris Marriott Rive Gauche Hotel

17 Boulevard Saint-Jacques, 75014 Paris - de 8h à 17h30

Vendredi

09DÉC

Tables rondes

ditep round-table 2016

To get the programm

and Dr. Jordi Remon (VHIO, Barcelona). We are looking forward to a big attendance for this round-table which will take place throughout the day on 9th December.

In addition, DITEP focuses on advances at the inter-face between early trials and tumour biology (in par-ticular, in the fields of immunotherapy and precision medicine). Conscious of this ambition and thanks to the support of the Clinical Research Committee, we launched the MOSCATO02 (Molecular Screening for CAncer Treatment Optimisation 02) trial by Dr. Antoine Hollebecque. It differs from MOSCATO01 in that it seeks to correlate DNA alterations (assessed by WES/RNA sequencing) with immunohistochemical characterisa-tion of the immune biomarkers (figures on left side). To achieve this objective, a major effort is required from the Biopathology Department, because the molecular biology results and the morphological and immunohis-tochemistry findings must be generated in real time, on average 21 days after the biopsy of the tumour.

Thus, 4 immunological markers will be analysed routi-nely in tumour biopsies: PD-L1, CD3, CD8 and FoxP3. These markers will sometimes be complemented by tests for MMR proteins as screening for microsatellite instability [MLH1, MSH2, MSH6 and PMS2]. We hope that MOSCATO02 will improve our understanding of interrelationships between tumour molecular abnor-malities and the immune system; and that it will also assist in better matching individual patients who are candidates for early trials to the phase I/II trials which are most relevant to them in relation to their biological data.

Prof. Jean-Charles Soria & Prof. Jean-Yves Scoazec

cd8+ lymphocyeswithin tumour cells

strong expression of pd-l1by tumour cells

(coll dr. J adam)

our oncological physicians presented encou-raging results from early trials and ditep precision medicine programmes at the eha (9-12 June 2016, copenhagen) and esmo (7-11 november 2016, copenhagen) congresses.

early trials with antibodies targeting over-expressed cell markers in certain cancersDr. Jean-Marie Michot reported preliminary results of the phase I trial of ARGX-110 at the EHA. This is a new monoclonal antibody tar-geting CD70 in patients with T-cell lympho-mas positive for CD70 (see abstract of poster). Promising results for ABBV-399, a conjugated antibody (or ADC) targeting c-Met, were pre-sented by Dr. Eric Angevin in a poster at the ESMO meeting (Abstract 317P).

new results from our precision medicine programmesProfessor Jean-Charles Soria’s team pre-sented two posters at the annual ESMO Congress: one by Dr. Loic Verlingue refer-red to the MOSCATO trial in patients with the ERBB3 mutation (Abstract 122P); the other by Dr. Linda Mahjoubi being based on results from the MOSCATO and Match-R trials (Abs-tract 1536P).

gustave roussy-sponsored early trials in lung cancer and melanomaTwo Gustave Roussy-sponsored early trials were the subject of poster presentations at the ESMO Congress: one from Dr. David Plan-chard on the combination tremelimumab/gefitinib in EGFR-mutated non-small cell lung cancer (Abstract 1245P); and the second reporting a trial directed by Professor Caro-line Robert combining radiotherapy and the anti-CTLA-4 agent ipilimumab in metastatic melanoma (Abstract 1117P).

three ditep oral presentations planned for the eortc-nci-aacr congressThe next international EORTC-NCI-AACR meeting devoted to novel anti-cancer the-rapies will be held in Munich from 29th November to 2nd December. The DITEP team will be participating in 3 oral sessions to present the following early trials: “First-in-human”, GDC-0994 (ERK1/2 inhibitor) to be presented by Dr. Andrea Varga 30th November; SAR408701, a conjugated antibody (anti-CEACAM5 ADC), by Dr. Anas Gazzah 1st December; and LY3039478, a Notch signalling pathway inhibitor, by Dr. Christophe Massard on 2nd December.

DITEP’S STRONG PRESENCEAT INTERNATIONAL CONGRESSES

congress

when should tkis be stopped in patients with cml in remission? A very long term follow-up study with the first-generation agent imatinib in CML was reported. The question posed by the euro-SKI study reported by J. Richter (SKI = stop kinase inhibitor) was how to define the conditions for cessation of TKI in patients in molecular re-mission. Long term tolerance remained ex-cellent and 6 years of treatment seemed an optimal period, after which one might try to stop the TKI. Significantly, if patients relapse, they will again be responsive to TKI.

efficacy of anti-pd1 agents (nivolumab and pembrolizumab) in refractory or re-lapsed hodgkin’s lymphoma is well known, but what is the situation with other lym-phoma types? The excellent news reported from the pembrolizumab phase IB trial, to which DITEP contributed, is that it is also very effective in primary mediastinal B-cell lymphoma. More than 80% of patients had a reduction in tumour volume and more than 40% an objective response. In particular, complete responses were of good quality and prolonged (see figure, female patient treated at DITEP in complete response for more than 2 years). Biopsies have helped in understanding the stricking responsiveness of Hodgkin’s lymphoma and mediastinal B-cell lymphoma, which are closely related in that they have molecular abnormalities in common such as 9p24 rearrangements involving PD1 ligands.

POST EHA 2016 : THE EUROPEAN HAEMATOLOGY CONGRESS 2016 PUT IN PERSPECTIVE WITH DITEP EARLY TRIALS

congress

Dr. Jean-Marie Michot

THE EARLY DRUG DEVELOPMENT PROGRAM OF THE PEDIATRIC AND ADOLESCENT ONCOLOGY DEPARTMENT OF GUSTAVE ROUSSY

currently 7 treatment arms are proposed with 5 new anticancer agents, 6 of them are combination therapies, covering cell cycle, pi3k/akt/mtor, dna double stranded break repair and immunotherapy.

the early drug development program of the pe-diatric and adolescent oncology department of gustave roussy, headed by dr birgit geoerger, is the largest center in europe with currently approximately 25 open early clinical trials.More than 40 patients are included per year in phase 1, multiple First-in-Child, or early phase 2 trials and 35 to 40 patients receive currently a mo-lecular profile of their recurrent tumor within our precision medicine program.The pediatric department has close interac-tions with the DITEP and both departments are an INCa-labeled CLIP2 center. Together with the pediatric partners Trousseau and Robert Debré Hospitals the Gustave Roussy CLIP2 offers ex-perimental therapeutics for all cancer patients, those with solid and hematological malignancies and from early childhood to adults. It allows for pediatric and adolescent patients to give access to innovative anticancer agents at a high profes-sional level while respecting a specific care envi-ronment. The main missions are aligned with those raised by the INCa within the Plan Cancer 3, to concep-tionalize, plan, conduct and analyze early clinical trials in oncology and hematology on a national and international level.In this regard, the pediatric partners of the CLIP2 have developed together with the INCa and phar-ma partners the AcSé-ESMART trial which is a proof-of-concept multi-arm trial where pediatric patients are included following a molecular pro-file in the MAPPYACTS trial using Whole Exome and RNA Sequencing and based on the molecular alteration detected. The European MAPPYACTS trial was developed following the monocentric ex-perience of MOSCATO-01 at Gustave Roussy, led by Jean-Charles Soria where pediatric patients were profiled jointly with adult cancer patients.

Currently 7 treatment arms are suggested with 5 new anticancer agents, 6 of them are combination therapies, covering cell cycle, PI3k/AKT/mTOR, DNA double stranded break repair and immuno-therapy. An innovative design and an enrichment strategy developed by Xavier Paoletti are applied to define optimal doses in a pediatric popula-tion and if a molecular alteration in the targeted pathway is of advantage to the patient population. MAPPYACTS and AcSé-ESMART are sponso-red by Gustave Roussy, funded by DHOS-PHRC, Fondation ARC, INCa, Imagine for Margo, Fondation Enfants et Santé and partners and par-ticipating Pharma.

Thanks to close collaboration efforts between the pediatric and the adult departments we have several adult trials in the DITEP that allow the inclusion of adolescent patients and we hope to intensify this approach.

interactions

Dr. Birgit Geoerger

Over more than ten years, targeted therapies have been making great strides in treatment of cancer, and still today new generation agents with considerable clinical effectiveness are being developed.

The Match-R trial commenced late in 2014 and up to now more than 125 patients have been re-cruited to it. It is a two-centre prospective trial sponsored by Gustave Roussy which intends to study evolution of the clonal architecture of tu-mours in patients treated with targeted thera-pies.

The Bégin Hospital and Gustave Roussy have collaborated to establish a sub-study of the MATCH-R trial focusing on cancer of the pros-tate (Dr. Yohann Loriot) in patients resistant to enzalutamide and abiraterone. Tests are com-pared with a double baseline-resistance biopsy.This protocol employs genomic and proteomic approaches to study mechanisms of acquisition of resistance using biopsies from patients after progression.

Several types of analysis are carried out:• Genetic (sequencing of the whole exome WES combined with a study of the transcriptome RNASeq)• Analysis of DNA repair mechanisms• Analysis of immune biomarkers mechanisms, with imminent recruitment of a cohort com-posed of patients treated with anti-PD1/-PDL1 (including a biopsy performed before treat-ment).

In parallel with direct study of biopsies from pa-tients, primary cultures and xenografts from tumour samples are being developed with the aim of validating functionally the information derived from tests on biopsies.

This trial runs in close collaboration with various Gustave Roussy departments:• MDs in DITEP who recruit patients.• The Department of Interventional Radiology which is skilled at of performing biopsies from virtually all metastatic tumour sites.• Translational research with Dr. Jean-Yves Scoazec, facilitating analysis of biopsy material in real time, performing the quality control (tumour cellularity) of the biopsy. Tumour DNA is extracted from the biopsy in Dr. Ludovic Lacroix’s laboratory (Ms Catherine Richon) and is sent for analysis to the Sequencing Department (Integragen) and to the Cytogenetics Laboratory (Dr. Nathalie Auger) for CGH.• The Statistics Department for the final analy-sis of trial results.• INSERM Unit U981 with Luc Friboulet.

analysis of the findings is discussed at a twice-monthly multidisciplinary team meeting so that the evolution of patient tumour ar-chitecture can be better understood. in this way, new mechanisms of resistance to targeted therapies will be identified, thus optimising matching of patients to the most effective the-rapeutic agents.

focus

MATCH-R

MATCH –R

Targeted therapy with res-ponse or stability followed by progression

Recoveryprevious biopsy

Inclusion InclusionBiopsy Biopsy

MATCH –R PROSTATE

Biopsyon progression

Targeted therapyImmune repsonse

or stability followedby progression on

Enzalutamide/Abiraterone

IMAGING/TGR AND EARLY TRIALS

focus

Agents which block immune checkpoints (anti-PD-1, anti-PD-L1) are now widely used in clinical prac-tice in various conditions, such as melanoma, non-small cell lung cancer and kidney, bladder and H&N cancers.Over 20 to 30% of patients treated by these drugs have objective tumour responses (partial or complete responses) which are usually of long-lasting, thus revolutionising the management of these patients. However, cases of rapid, paradoxical tumour progression («hyperprogression») on treatment with these same agents have been reported anecdotally.We recently studied a total of 131 patients treated with anti-PD-1 / PD-L1 in phase I clinical trials at Gustave Roussy. All of these patients were assessable for a Tumour Growth Rate (TGR) calculation on data acquired before initiation of treatment (“reference period”) and during treatment (“experimental period”). We identified a sub-group (12 patients, 9%) with rapidly progressive disease (RPD), defined as having progression according to RECIST (response evaluation criteria in solid tumours) and at least a doubling of TGR during the experimental periods.The RPD phenotype was not associated with stage of disease, tumour type or type of drug received (anti-PD-L1, anti-PD-1). However, RPD patients were older (potential effect of immunity in the elderly patient which differs from that in the young) and had a lower overall survival rate. In summary, this no-vel mode of progression emphasises that it is important to develop biomarkers of efficacy for the new immunotherapies.

Dr. Rastislav Bahleda

final results of the moscato-01* study: first demonstration of precision medicine benefit

The final results of the MOSCATO-01 study have been presented by Jean-Charles Soria at the MAP meeting (London, Sept 23rd, 2016). This Gustave Roussy-sponsored biomedical research exploited the extensive molecular 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 therapy. Over 1011 patients were included between Nov 2011 and March 2016. Four hundred eleven patients had an “actionable” molecular abnormality (identified 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 objective of the study was to demonstrate that the progression-free survival of the first line of oriented treatment (PFS2) was significantly 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 me-dian overall survival of 11.3 months. With these results, MOSCATO-01 is the first trial demonstrating a clinical benefit in advanced cancer patients by a large-scale molecular screening and precision medicine.

* MOlecular Screening for CAncer Treatment Optimization approach.

Drs. Charles Ferté, Samy Ammari, Laurent Dercle, Stephane Champiat

OUR RECENT PUBLICATIONS

news

> immunotherapies, immunomodulators• SAR3419 (anti-CD19) coupled to maytansine, in combination with rituximab in diffuse large B-cell lymphoma (phase II): Coiffier B, et al. Br J Haematol. 2016; 173(5): 722-30. See abstract.

• Pembrolizumab (anti-PD-1) in melanoma: Ribas A, et al. JAMA. 2016; 315: 1600-1609. See abstract.

• Pembrolizumab (anti-PD-1) in Hodgkin’s lymphoma: Armand P, et al. J Clin On-col. [Epub ahead of print]. And case study by Michot JM, et al. Eur J Cancer. 2016; 66: 91-4. See abstract.

• Durvalumab (anti-PD-L1) dans le cancer de la vessie : Massard C, et al. J Clin Oncol. [Epub ahead of print]. See abstract.

• DCombination of chemo-radiotherapy and the antiviral agent cidofovir in cancer of the uterine cervix (Trial sponsored by Gustave Roussy): Deutsch E, et al. Oncotarget. 2016; 7(18): 25549-57. d of print]. See abstract.

> targeted therapies• Combined plitidepsin / bevacizumab in refractory solid tumours: Aspeslagh S, et al. Anticancer Drugs. [Epub ahead of print]. See abstract.

• SAR405838 (HDM2 inhibitor) in liposarcoma: Jung J, et al. Nat Commun. 2016; 7: 12609. See abstract.

• CC-115 (double inhibitor TORK/DNA PK) in chronic lymphatic leukaemia: Thijssen R, et al. Blood. 2016; 128: 574-583. See abstract.

> precision medicine• MATCH-R and resistance to crizotinib in cancer with MET gene mutation: Benderra MA, et al. J Thorac Oncol. 2016; 11(2):e21-3. See abstract.

• MATCH-R and resistance to crizotinib in non-small cell lung cancer with the ROS1 mutation: Facchinet-ti F, et al. Clin Cancer Res [Epub ahead of print]. See abstract.

• MOSCATO (Molecular Screening for Cancer Treatment Optimization): Postel-Vinay S, et al. Ann Oncol. 2016; 27(2): 344-52. See abstract.

TAT CONGRESS 2017: CO-ORGANISED BY GUSTAVE ROUSSYThe 15th TAT Congress will be held in Paris from 6 to 8 March 2017 under the chairmanship of Profes-sor Jean-Charles Soria. This is the first international meeting devoted to early trials in oncology. It offers researchers and biotechnology companies a unique opportunity to meet and talk with world leaders in early clinical research about new targeted therapies and novel treatments in oncology.

MOLECULE PROTOCOLE PROMOTEUR TARGET

ABBV-399 M14-237 Abbvie Anti-MET mAb-drug (MMAE) conjugate

ABBV-085 M15-394 Abbvie Anti-LRRC15 mAb-drug (MMAE) conjugate

AG120 AG120-C-002 Tumeurs solides Agios IDH1 inhibitor

AG120 AG120-C-001 Hemato Agios IDH1 inhibitor

AG221 AG221 - C - 001 Agios IDH2 inhibitor

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

AZD5363 D3610C00001 Astrazeneca AKT inhibitor

AMG 228 AMG 228 -20140131 Amgen Agonistic anti-GITR mAb

AMG 232 AMG232 FIH_CSET 2013-2094 Amgen MDM2 inhibitor

Aplidine + Bortezomide APL-A-012-013 Pharmamar Cyclic Depsipeptide +Proteasome inhibitor

ARGX-110 ARGX-110 -1201 Argen-X IgG1 defucosylised anti-CD70 mAb

Avelumab B9991004 Pfizer IgG1 anti PD-L1 mAb

AZD6738 D5330C00004 AstraZeneca ATR inhibitor

BAY 1125976 BAY AKT 16647 Bayer AKT1 inhibitor

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

BIBW2992Docetaxel + Cisplatine GORTEC 2013-01 TAPIS Gortec Irreversible EGFR and

HER2 inhibitor

BLU-285 BLU-285-1101 Blueprint KIT inhibitor

BYL719 CBYL719Z2102 Novartis PI3K inhibitor

CC-122CC-122-ST-001

CC-122-NHL-001 Celgene Pleiotropic Pathway Modifier (PPM)

CC-122CC-223CC-292

CC122 DLBCL Celgene

Pleiotropic Pathway Modifier (PPM)

mTOR & BTK inhibitor

Crizotinib Acsé Unicancer TK (ALK et MET) inhibitor

E7046 E7046-G000-101 Esai Prostaglandin E2 receptor 4 (EP4) antagonist

GDC-0032 GO00886 Genentech PI3K inhibitor

GDC-0575 GP28153 Genentech CHK1 inhibitor

GSK2816126 117208 GSK Inhibiteur de l’histone-lysine N-méthyl transférase EZH2

GSK2879552 200858 SCL LSD1 GSK LSD1 inhibitor

GSK3174998 201212 GSK Agonistic IgG1 anti-OX40 mAb

INC280 + EGF816 CINC280X2105C Novartis MET + EGFR T790M inhibitors

IPH2201 IPH2201-203 Innate Pharma Anti-NKG2A mAb

JNJ-42756493 42756493EDI1001 J&J PanFGFR: 1, 2, 3, 4 inhibitor

LEE011 + INC424+ PIM447 CPIM447X2104C Novartis JAK 1&2 + CDK 4/6 + PIM inhibitors

LTX 315 C12-315-03 Lytix Biopharma Immunostimulating lytic peptide

trials portfolio

LY3009120 I6X-MC-JBDA Lilly PanRAF inhibitor

LY3039478 I6F-MC-JJCA Lilly NOTCH inhibitor

LY3127804 + Ramucirumab I7W-MC-JQBA Lilly IgG4 anti-Ang2 mAb + IgG1 anti-VEGFR2 mAb

MAG-Tn3 + AS15 Matrivaccin Pasteur MAG-Tn3 active immunization

MEDI0562 + MEDI4736 (Durva-lumab)

ou TremelimumabD6060C00002 Medimmune

Agonistic IgG1 anti-OX40 mAb +IgG1 anti PD-L1 mAb ou

IgG2 anti CTLA-4 mAb

MEDI4736(durvalumab) MedI 4736-1108 MedImmune IgG1 anti PD-L1 mAb

MEDI4736 (durvalumab) + Olaparib Mediola Medimmune IgG1 anti PD-L1 mAb + PARP

inhibitor

MEDI4736 (durvalumab) +/- tremelimumab ou AZD9150 D4190C00023 Medimmune

IgG1 anti PD-L1 mAb +/-IgG2 anti CTLA-4 ou STAT3an-

tisense oligonucleotide inhibitor

MK-3475(pembrolizumab) MK-3475-013 MSD IgG4 anti PD-1 mAb

MK-3475(pembrolizumab) MK-3475-028 MSD IgG4 anti PD-1 mAb

MK-8628 MK-8628-006 MSD BET inhibitor

MLN0128 + MNL2480 + Alisertib C28002 Takeda Pan Raf/mTOR/Aurora A Kinase

inhibitor

MOXR0916 + MPDL3280A (atezolizumab) GO 29674 Genentech Agonist IgG1 anti-OX40 mAb +

IgG4 anti PDL1 mAb

MPDL3280A(atezolizumab) +

ErlotinibWP29158 Roche IgG4 anti-PDL1 mAb + EGFR

inhibitor

MPDL3280A(atezolizumab) +

RO5509554BP29428 Roche IgG4 anti-PDL1 mAb + IgG1

anti-CSF1R mAb

NBTXR3 NBTXR3-103 Nanobiotix Nanoparticles + radiotherapy

Necitumumab + Abemaciclib I4X-MC-JFCU Lilly EGFR alpha-CDK4/6 inhibitor

Necitumumab + Pembrolizumab I4X-MC-JFCQ Lilly IgG1 anti-EGFR mAb + IgG4

anti-PD1 mAb

Nivolumab CA 209-358 BMS IgG4 anti-PD1 mAb

ODM 204 DUALIDES Orion Androgen Receptor/CYP17A1 inhibitor

ORY-1001 CL01-ORY-1001 Oryzon Genomics LSD1 inhibitor

OTX015 OTX015_108 MSD BET inhibitor

Panitumumab + Dabrafenib +Trametinib MEK116833 GSK IgG2 anti-EGFR mAb +

BRAF & MEK/ERK inhibitor

PCA062 CPCA062X2101 Novartis Anti-P-CADHERIN mAb-drug (DM1) conjugate

PDR001 CPDR001X2101 Novartis IgG4 anti-PD1 mAb

RO5520985 +/- MPDL3280A (atezolizumab) BP28179 Roche IgG4 anti-Ang2 mAb + IgG1

anti-PDL1 mAb

RO7009789 + MPDL3280A (atezolizumab) BP29392 Roche Agonistic IgG4 anti-CD40 mAb +

IgG1 anti-PDL1 mAb

S55746 CL1-55746-001 Servier BCL2 inhibitor

SAR408701 TED 13751 Sanofi Anti-CEA-CAM5 mAb-drug (DM4) conjugate

SAR428926 TED 14147 Sanofi Anti-LAMP1 mAb-drug (DM4) conjugate

S 95005 + oxaliplatine CL1-95005-001 Servier Trifluridine/tipiracil hydrochloride

TAS 114+ S1 TAS 114 Taiho dUTPase inhibitor + S1

TAS 120 TAS-120-101 Taiho FGFR inhibitor

Urelumab + Nivolumab CA186-107 BMS Agonistic IgG4 anti-CD137 mAb + IgG4 anti-PD1 mAb