IGCS Translational - Cervical cancer Chicago May 28th, 2015

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1 IGCS Translational - Cervical cancer Chicago May 28th, 2015 Precision medicine in cervical cancer

2 BioRAIDs and molecular data France Expected 150

3 Present status internationally n=142 May 2015 Expected n=450 May 2016 TOTAL to be included n=500 end: April 2017 n Rates : 20 /month We need 25 /month Achievable via centres which opened recently and more centres to open

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11 Detection of Copy Number Alteration, from exome sequencing data

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16 Perspectives: data integration

17 Immunology platform 1 molecular diagnostics of frozen tumour sample: MHC mutated: what does that entail? Which pathway (s) drive(s) the tumor can we get by using ct DNA? (Els Berns) 2 impact on tumor micro-environment: Specific patterns? SME: ZKW Hannover fixed tissue 3 study of immunological cells: live cells tumor and blood: ELISPOTS etc.

18 Immunology platform 1 molecular diagnostics of frozen tumour sample: MHC mutated: what does that entail? Which pathway (s) drive(s) the tumor can we get by using ct DNA? (Els Berns) 2 impact on tumor micro-environment: Specific patterns? SME: ZKW Hannover fixed tissue 3 study of immunological cells: live cells tumor and blood: ELISPOTS etc.

19 A randomized phase II study of HPV therapeutic vaccine Transgene TG4001 combined with anti-pd-1 antibody for patients with cervical cancer

20 RATIONALE for TG4001 vaccine Over 90% of cervical cancer patients are positive for HPV viral antigen 60-65% of HPV16. TG4001 vaccine : MVA modified poxvirus carrying and expressing mutation-inactivated human papilloma virus 16 (HPV16) E6 and E7 oncoproteins human interleukin-2. In phase II clinical trials, TG4001 demonstrated safety and promising clinical response and efficacy in 50% of women with CIN2/3 lesion caused by HPV16. Cross reactivity in viral types other than HPV16 all high risk HPV types according to the Roche linear array diagnostics test can be included in a therapeutic vaccine trial HPV genotypes include: 6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 45, 51, 52, 53, 54, 55, 56, 58, 59, 61, 62, 64, 66, 67, 68, 69, 70, 71, 72, 73 (MM9), 81, 82 (MM4), 83 (MM7), 84 (MM8), IS39, and CP6108 (high-risk viral types are in bold).

21 Rationale: mouse models and clinical trials Antibodies blocking PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads ultimately to tumor rejection, either as a monotherapy or in combination with other treatment modalities. PD-1 blockade has shown to be useful in many cancers, including cervical cancers and is expected to prolong survival sigificantly

22 Combination trial Expected to significantly increase patient survival Vaccine increases pool of reactive T cells Checkpoint inhibitor prolongs their lifespan

23 Patient population Patients in complete clinical response at 4-6 months have excellent survival statistics >90% Patients in incomplete response following standard therapy have a poor PFS at 2 years <50%. Our aim is to improve PFS statistics

24 Median PFS

25 Poor response and correct treatment: only 35 pts Radio chemotherapy + hysterectomy Radiotherapy only + hysterectomy

26 Statistical assumptions Phase 2 multicenter non-comparative randomized trial The primary endpoint PFS 12 months. Fleming one-stage increase PFS at 12 months from 0.40 to 0.60 hazard ratio of 1.8 (under the exponential assumption) 80 patients to be included in the experimental treatment arm; 40 patients in the control arm

27 Efficacy 40 patients or more free of events at 12 months (50%) in experimental arm efficacy of the trial with a 0.05 type I error rate and 97% of power 2:1 limit the sample size to 40 patients in the standard treatment arm control arm to evaluate the accuracy of the null hypothesis

28 Stratification According to the FIGO stage stage 4 vs others stages stage 4 disease stratum limited to 20% of patients

29 Randomisation 2:1 into the experimental or control arm: Experimental Arm: Combined injection of TG4001 and MK Control Arm: Standard care Taxol Carbo Any chemotherapy doublet : GOG 204: Tewari, 2009 Avastin allowed cost by investigator centre.

30 Phase 2 trial and run-in phase Primary Objective PFS by combination of MK-3475 with TG patients to validate safety After the first 20 patients, toxicity monitored in a continuous fashion by data safety management board

31 Secondary Objectives.1 Safety of combination Biological activity of the combination Correlate to clinical response. Overall response rate and best overall response in patients with residual tumor using the modified Immune-Related Response Criteria (irrc), and response duration. Overall survival (OS).

32 Secondary objectives. 2 Analyses of T-cell populations in peripheral blood samples (flow cytometry) Screen for Association between tumor programmed death ligand 1 (PD-L1) expression Response PD-L1 expression in the tumor specific microenvironment

33 ENDPOINTS Primary endpoint progression free survival at 12 (or 18?) * months. Median PFS (GOG 204) in advanced/refractory/stage 4 patients treated by chemotherapy doublets is 6-8 months. Median progression free survival of the Kunos population (which remains operable after radio chemotherapy) with residual disease at the time of surgery is 18 months. Median progression free survival of patients who had a suboptimal primary treatment (e.g. radiotherapy without chemotherapy) is inferior.

34 Secondary endpoints HPV specific T cell immunity Assays to be defined: cell sorting for tetramers cytocheck tubes CLINICAL EVALUATION Safety Response rate, best overall response and response duration Survival (OS)

35 Secondary endpoints.2 CIRCULATING IMMUNE RESPONSIVE CELLS Evaluation of circulating T cells : flow cytometry and phenotyping (cytocheck tubes) {Peguillet, 2014} NKT cells as biomarkers of non-response (CD16,CD56,CD59) (Transgene ref)

36 Secondary endpoints.3 TUMOUR microenvironment pre and post vaccination in biopsiable tumors analysis by Zellkraftwerk/ Hannover or Curie academic team, on fixed biopsies; pretumour evaluation already available from BioRAIDs patients association between programmed death ligand 1 (PD-L1) expression in tumor and response.

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38 3 REAGENTS Propulsion: antigen as fuel Lift/wings: avoid crosswinds in the tumor microenvironment Balanced center of gravity and weight: checkpoint modification FOR CONTROLLED FLIGHT Principals of antitumor immune response

39 IGCS Translational - Cervical cancer Chicago May 28th, 2015 Precision vaccines in cervical cancer

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