ADO-Studientreffen Melanom Adjuvant/Neoadjuvant ZDO. Thomas Eigentler Dresden,

Transkript

1 ADO-Studientreffen Melanom Adjuvant/Neoadjuvant ZDO Thomas Eigentler Dresden,

2 ZDO Stadium II

3 ZDO EORTC Adjuvant Pegylated-Interferon-alpha2b (Sylatron TM ) for 2 Years Versus Observation in Patients With an Ulcerated Primary Cutaneous Melanoma With T(2-4)bN0M0: a Randomized Phase III Trial of the EORTC Melanoma Group Patienten mit ulzerierten Primärmelanomen haben eine ungünstigere Prognose (AJCC 2010) In Vorstudien haben Patienten mit ulzerierten Primärmelanomen in Subgruppenanalysen besonders von einer ajduvanten Therapie profitiert

4 EORTC PEG-Intron Observation After Regional Lymph Node Dissection in AJCC Stage III (TxN1-2M0) Melanoma Patients: a Randomized Phase III Trial ZDO * Nur Patienten mit Mikrometastasen im SN

5 EORTC PEG-Intron Observation After Regional Lymph Node Dissection in AJCC Stage III (TxN1-2MO) Melanoma Patients: a Randomized Phase III Trial ZDO Firstline Patients with an ulcerated melanoma with Breslow >1 mm, N0M patients stages IB-IIC tumor-free R A N D O M I Z A T I O N 1:1 ARM A Biological: PEG IFN alfa-2b 3µg/kg weekly injections for 2 y. ARM B No Intervention: Observation

6 EORTC Adjuvant Pegylated-Interferon-alpha2b (SylatronTM) for 2 Years Versus Observation in Patients With an Ulcerated Primary Cutaneous Melanoma With T(2-4)bN0M0: a Randomized Phase III Trial of the EORTC Melanoma Group ZDO Primary Outcome Measures: Relapse-free survival (RFS) [Time Frame: 6.3 years from first patient in] Secondary Outcome Measures: Occurrence of Adverse Events [Time Frame: 6.3 years from first patient in] Overall survival (OS) [Time Frame: 7.8 years from first patient in] Distant metastases-free survival (DMFS) [Time Frame: 7.8 years from first patient in] Quality of life [Time Frame: 6 years from first patient in]

7 EORTC Adjuvant Pegylated-Interferon-alpha2b (Sylatron TM) for 2 Years Versus Observation in Patients With an Ulcerated Primary Cutaneous Melanoma With T(2-4)bN0M0: a Randomized Phase III Trial of the EORTC Melanoma Group ZDO Inclusion Criteria: Subjects must be between years old. Subjects must have histologically documented ulcerated primary cutaneous melanomas with T(2-4)b N0M0. Adequate resection of ulcerated primary cutaneous melanoma. 1 to 2 cm normal tissue excision margins according to Breslow thickness are recommended. SNB must occur within 12 weeks prior randomization. Subjects must have an ECOG performance status of 0 or 1 Subjects must have adequate bone marrow, renal and hepatic function as defined by the following parameters obtained up to maximum 12 weeks prior to randomization: WBC >= 3.0 x 109/L Neutrophils > 1.5 x 109/L Platelets > 100 x 109/L Hemoglobin >= 9 g/dl or 5.6 mmol/l Adequate Renal and Hepatic function: Serum creatinine < 2.0 mg/dl or < 140 µmol/l SGOT and SGPT < 2 times upper normal limit of laboratory normal (ULN)

8 EORTC Adjuvant Pegylated-Interferon-alpha2b (Sylatron TM) for 2 Years Versus Observation in Patients With an Ulcerated Primary Cutaneous Melanoma With T(2-4)bN0M0: a Randomized Phase III Trial of the EORTC Melanoma Group ZDO Exclusion Criteria: No mucosal melanoma nor ocular melanoma. No evidence of nodal involvement confirmed by sentinel lymph node biopsy (SNB). Sentinel Node staging after the excision of the primary must be done between the date of final excision of the primary and the date of randomization. No evidence of regional nor distant lymph node metastases nor satellites/intransit metastases (even if they have been resected). No evidence of distant metastasis on clinical examination, CT/MRI of full chest, abdomen and pelvis. Neck CT/MRI if head and neck primary. No clinical evidence of brain metastasis.

9 ZDO EORTC Adjuvant Pegylated-Interferon-alpha2b (Sylatron TM) for 2 Years Versus Observation in Patients With an Ulcerated Primary Cutaneous Melanoma With T(2-4)bN0M0: a Randomized Phase III Trial of the EORTC Melanoma Group Essen Kiel Lübeck Köln Heidelberg Mainz Mannheim Würzburg

10 ZDO Stadium III

11 EORTC Adjuvant Immunotherapy With Anti-CTLA-4 Monoclonal Antibody (Ipilimumab) Versus Placebo After Complete Resection of High Risk Stage III Melanoma: A Randomized, Double-blind Phase 3 Trial of the EORTC Melanoma Group ZDO The Lancet Oncology , DOI: ( /S (15) )

12 EORTC Adjuvant Immunotherapy With Anti-CTLA-4 Monoclonal Antibody (Ipilimumab) Versus Placebo After Complete Resection of High Risk Stage III Melanoma: A Randomized, Doubleblind Phase 3 Trial of the EORTC Melanoma Group ZDO

13 MK / EORTC-1325 Adjuvant Immunotherapy With Anti-PD-1 Monoclonal Antibody Pembrolizumab (MK- 3475) Versus Placebo After Complete Resection of High-risk Stage III Melanoma: A Randomized, Double- Blind Phase 3 Trial of the EORTC 900 patients stage IIIA(1mm+; max. 20%)-IIIC No evidence of disease no intransit-mets tumor tissue required (PDL-1 expression) Node-dissection performed according to guidelines R A N D O M IZ A TI O N 1:1 ARM A Pembrolizumab 200mg IV Q3 for 1 Year ARM B Placebo IV Q3 for 1 Year Crossover possible after PD ZDO Primary Objectives: Recurrence-free survival (also in the subgroup of patients with PD-L1-positive tumor expression)

14 MK / EORTC-1325 Adjuvant Immunotherapy With Anti-PD-1 Monoclonal Antibody Pembrolizumab (MK- 3475) Versus Placebo After Complete Resection of High-risk Stage III Melanoma: A Randomized, Double- Blind Phase 3 Trial of the EORTC Major Inclusion criteria: Completely resected Stage III melanoma Tumor tissue available for evaluation of PD-L1 expression ECOG performance status of 0 or 1 Adequate organ function No prior therapy for melanoma except surgery for primary melanoma lesions (or previously treated with interferon for thick primary melanomas without evidence of lymph node involvement are eligible) Major Exclusion criteria: Mucosal or ocular melanoma History of pneumonitis requiring treatment with steroids, interstitial lung disease History of hematologic or primary solid tumor malignancy, unless no evidence of that disease for 5Y Active autoimmune disease that has required systemic treatment in past 2 years Active infection requiring therapy Unstable hyperthyroidism or hypothyroidism Diagnosis of immunodeficiency Systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication Known history of human immunodeficiency virus (HIV), active Hepatitis B or C ZDO

15 MK / EORTC-1325 Adjuvant Immunotherapy With Anti-PD-1 Monoclonal Antibody Pembrolizumab (MK- 3475) Versus Placebo After Complete Resection of High-risk Stage III Melanoma: A Randomized, Double- Blind Phase 3 Trial of the EORTC ZDO

16 ZDO

17 ZDO MK / EORTC-1325 Adjuvant Immunotherapy With Anti-PD-1 Monoclonal Antibody Pembrolizumab (MK- 3475) Versus Placebo After Complete Resection of High-risk Stage III Melanoma: A Randomized, Double- Blind Phase 3 Trial of the EORTC Country Number of sites interested Expected enrollment per year Australia Austria 2 20 Belgium 3 28 Czech Republic 1 15 Denmark 3 80 Finland 1 20 France Germany Russia 3 70

18 ZDO MK / EORTC-1325 Adjuvant Immunotherapy With Anti-PD-1 Monoclonal Antibody Pembrolizumab (MK- 3475) Versus Placebo After Complete Resection of High-risk Stage III Melanoma: A Randomized, Double- Blind Phase 3 Trial of the EORTC Dear Investigators, This is a reminder that we plan to close screening tomorrow 27-Jul :59 PM PDT. No additional patients will be allowed to screen in the study. IMPORTANT REMARKS: 1) Patients who have signed consent on or before 27-Jul should be registered in ORTA as soon as possible. 2) Patients can only be registered (STEP 1) if they have consented and if surgery has been performed. If you have a problem enrolling patients as per above remarks, please contact the medical monitor. Kind regards, EORTC, Merck and Covance study team

19 ZDO Stadium IV

20 IMMUNED A Phase II Randomized, Double-Blind Trial of Immunotherapy With Nivolumab or Nivolumab Plus Ipilimumab Versus Double-Placebo Control as a Post-Surgical/Post- Radiation Treatment for Stage IV Melanoma With No Evidence of Disease Screening/Baseline/Pre-Examination (3 weeks before start of treatment) Incl. shipment of tumor tissue to the central lab in Essen for confirmation of PD-L1 status Randomization Arm A Nivolumab Monotherapy Treatment week 1-12 Arm B Nivolumab + Ipilimumab Therapy Arm C Double Placebo Control From week 12 onwards (2-weekly infusion of Nivolumab/Placebo) max. 1 year every 6 weeks: TraFo samples every 12 weeks: staging, ECOG, physical examination (see protocol for details) End of treatment visit Follow-Up: every 3 months after last treatment (until end of study) ZDO End of study: LPLV FU of LP for a maximum of 2 years

21 IMMUNED A Phase II Randomized, Double-Blind Trial of Immunotherapy With Nivolumab or Nivolumab Plus Ipilimumab Versus Double-Placebo Control as a Post-Surgical/Post- Radiation Treatment for Stage IV Melanoma With No Evidence of Disease Study Arm w1 w2 w3 w4 w5 w6 w7 w8 w9 w10 w11 w12 A Nivo 3mg/kg + Ipi- Placebo Nivo 3mg/kg Nivo- Placebo + Ipi-Placebo Nivo 3mg/kg Nivo 3mg/kg + Ipi- Placebo Nivo 3mg/kg Nivo- Placebo + Ipi- Placebo Nivo 3mg/kg B Nivo 1mg/kg + Ipi 3mg/kg Nivo- Placebo Nivo 1mg/kg + Ipi 3mg/kg Nivo- Placebo Nivo 1mg/kg + Ipi 3mg/kg Nivo- Placebo Nivo 1mg/kg + Ipi 3mg/kg Nivo- Placebo C Nivo- Placebo + Ipi- Placebo Nivo- Placebo Nivo- Placebo + Ipi- Placebo Nivo- Placebo Nivo- Placebo + Ipi- Placebo Nivo- Placebo Nivo- Placebo + Ipi- Placebo Nivo- Placebo followed by maintenance therapy: Nivolumab/Nivolumab-Placebo 2 weekly for up to 1 year or progression Cross-over OPTION for subjects in the Double-Placebo control cohort (arm C): Upon documented disease progression in the ecrf (confirmed via tumor assessment using radiologic imaging), subjects in Arm C may receive Nivolumab 3mg/kg monotherapy every 2 weeks until subsequent progression or for up to 1 year, whichever occurs first. ZDO

22 IMMUNED A Phase II Randomized, Double-Blind Trial of Immunotherapy With Nivolumab or Nivolumab Plus Ipilimumab Versus Double-Placebo Control as a Post-Surgical/Post- Radiation Treatment for Stage IV Melanoma With No Evidence of Disease Primary Objective: Estimate the efficacy of Nivolumab alone or in combination with Ipilimumab therapy in stage IV patients with no evidence of disease i.e. the primary endpoint is progression-free survival (PFS). Major Inclusion Criteria: Stage IV melanoma arising from a primary cutaneous site or metastatic from an unknown primary site with no evidence of disease (NED) after surgery or radiation therapy (conducted within 8 weeks before enrolment) Known BRAF status Minimum life expectancy of five years excluding their melanoma diagnosis ECOG performance status of 0 or 1 Tumor tissue from the resected site of disease must be provided for biomarker analyses. In order to be randomized a subject must have a PD-L 1 expression classification (positive ( 5% tumor cells expressing PD-L1) or negative (< 5% tumor cells expressing PDL1)). Major Exclusion Criteria: History of primary uveal or mucosal melanoma Prior therapy with CTLA4 or PD1 antibodies Any immunosuppressive therapy given within the past 30 days prior to study drug administration (excluding physiologic steroid hormone replacement) Known to be positive for HIV or other chronic infections (HBV, HCV). ZDO

23 IMMUNED A Phase II Randomized, Double-Blind Trial of Immunotherapy With Nivolumab or Nivolumab Plus Ipilimumab Versus Double-Placebo Control as a Post-Surgical/Post- Radiation Treatment for Stage IV Melanoma With No Evidence of Disease ZDO Teilnehmende Zentren Mannheim Hannover Buxtehude Regensburg Heilbronn Berlin Münster Gera München Dresden Ludwigshafen Essen Lübeck Mainz Erfurt Tübingen Leipzig Heidelberg Kiel Minden Frankfurt

24 MO28848 / EADO-NEO-VC Neoadjuvant Treatment With the Combination of Vemurafenib and Cobimetinib (GDC-0973) in Limited Metastasis of Malignant Melanoma (AJCC Stage IIIC/IV) and Integrated Biomarker Study: a Single Armed Phase II EADO ZDO

25 MO28848 / EADO-NEO-VC Neoadjuvant Treatment With the Combination of Vemurafenib and Cobimetinib (GDC-0973) in Limited Metastasis of Malignant Melanoma (AJCC Stage IIIC/IV) and Integrated Biomarker Study: a Single Armed Phase II EADO Endpoints: Primary Endpoint: Percent of patients who actually become resectable and are resected Secondary Endpoint: Progression-free survival, Overall survival(os), Safetytolerability, Inclusion criteria: Adult patients, 18 years of age Metastatic melanoma, stage IIIC or IV (AJCC 2010) ECOG 0-1 MAP-kinase pathway inhibitor treatment-naïve Positive for BRAF V600 mutation, preferentially to be shown from metastatic tumor tissue Exclusion criteria: Candidates for direct surgery: patients with single site easily resectable metastasis Major surgical procedure or significant traumatic injury within 2 weeks prior to first dose of study drug treatment Active central nervous system metastases except metastases after complete resection or stereotactic irradiation and stable status for at least 3 months ZDO

26 MO28848 / EADO-NEO-VC Neoadjuvant Treatment With the Combination of Vemurafenib and Cobimetinib (GDC-0973) in Limited Metastasis of Malignant Melanoma (AJCC Stage IIIC/IV) and Integrated Biomarker Study: a Single Armed Phase II EADO ZDO Teilnehmende Zentren Hannover Buxtehude Essen Mainz Tübingen Kiel

27 ZDO 214 Patienten, 1:1 Follow-Up PH-L19IL2TNF-02/15 Randomisierte, offene, kontrollierte, multizentrische Phase III Studie zur Bestimmung der Wirksamkeit der neoadjuvanten intratumoralen Behandlung mit L19IL2/L19TNF gefolgt von chirurgischer Entfernung der Läsionen im Vergleich zu chirurgischer Entfernung alleine in Melanom-Patienten der klinischen Stufe III B/C Stadium IIIb/c Operabel Kumulativ mind. 1 cm Tumordurchmesser Alle Läsionen injizierbar 4 Injektionen, 1xWoche, Op 4 innerhalb 4 Wochen Op innerhalb 4 Wochen

28 ZDO PH-L19IL2TNF-02/15 Endpoints: Primary Endpoint: RFS rate after 1 year of randomization Secondary Endpoint: Local RFS and DMFS after 1 year of randomization, RFS (2-/3-Y RFS), OS Safety Biomarkers Inclusion criteria: Adult patients, 18 years of age Metastatic melanoma, stage IIIB/C eligible for surgery (AJCC 2010) At least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (>= 10mm in longest diameter) or multiple injectable lesions that in aggregate have a longest diameter of >=10mm. ECOG 0-1 Exclusion criteria: Distant metastases Uveal or mucosal melanoma

29 PH-L19IL2TNF-02/15 Randomisierte, offene, kontrollierte, multizentrische Phase III Studie zur Bestimmung der Wirksamkeit der neoadjuvanten intratumoralen Behandlung mit L19IL2/L19TNF gefolgt von chirurgischer Entfernung der Läsionen im Vergleich zu chirurgischer Entfernung alleine in Melanom-Patienten der klinischen Stufe III B/C ZDO Teilnehmende Zentren Hannover Essen Heidelberg Tübingen Kiel

30 PV10-MM-31 PV-10 Intralesional Injection vs Systemic Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma 225 Patienten, 2:1 Follow-Up Recurrent, satellite or in-transit locally advanced cutaneous or subcutaneous melanoma metastases (AJCC Stage IIIB, IIIC or Stage IV M1a with no active nodal metastases) At least 1 cutaneous Target Lesion (each lesion > =10 mm in longest diameter or up to 5 lesions having a sum of longest diameters >= 10 mm). ZDO PV-10 to all study lesions d1, q28 until CR, PD or study termination. DTIC (iv. 850 m/m2) or TMZ (po. 200 mg/m2 for 5 days), q28 or Intralesional T-VEC on an initial 21 interval followed by consecutive 14 day intervals, until CR, PD or study termination occurs.

31 ZDO PV10-MM-31 PV-10 Intralesional Injection vs Systemic Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma Endpoints: Primary Endpoint: Progression-free survival (PFS) Secondary Endpoint: Complete response rate, Duration of complete response, OS Safety and tolerability Inclusion criteria: Age 18 years or older, male or female Recurrent, satellite or in-transit locally advanced cutaneous or subcutaneous melanoma metastases At least 1 cutaneous Target Lesion (each lesion > =10 mm in longest diameter or up to 5 lesions having a sum of longest diameters >= 10 mm). Target Lesions should be at least 10 mm from any other lesion No lesion > 30 mm in longest diameter; and no more than 50 lesions Performance Status: Eastern Cooperative Oncology Group (ECOG) 0-2 Exclusion criteria: Presence or history of visceral melanoma metastasis Presence of active nodal metastases

32 ZDO PV10-MM-31 PV-10 Intralesional Injection vs Systemic Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma Teilnehmende Zentren Kiel Hannover Essen Quedlinburg Tübingen Dresden Mainz Berlin

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34 Melanom palliativ Immunonkologisch Ralf Gutzmer Klinik für Dermatologie, Allergologie und Venerologie H TZH Haut- Tumor- Zentrum Hannover Abteilung und/oder Titel Abteilung und/oder Titel Datum

35 Gliederung T-VEC T-VEC Monotherapie T-VEC plus Ipilimumab T-VEC plus Pembrolizumab Keynote 252 (MSD/Merck) BoneMet (IIT, Hannover/Essen) H TZH

36 Was ist T-VEC? Talimogene Laherparepvec Modifiziertes Herpesvirus H TZH

37 Effekte von T-VEC Lawler&Chiocca, J Clin Oncol 2015 H TZH

38 T-VEC: Monotherapie-Studie (Study T-Vec ) Multicenter, Open-label, Single-arm Trial to Evaluate the Correlation Between ORR and Baseline Intratumoral CD8+ Cell Density in Subjects With Unresected Stage IIIB to IVM1c Melanoma Treated With T-Vec Primärer Endpunkt: Korrelation zwischen ORR und intratumoraler CD8+ Zell-Dichte vor Therapie H TZH

39 H TZH T-VEC: Monotherapie-Studie (Study T-Vec )

40 T-VEC: Monotherapie-Studie (Study T-Vec ) Estimated Enrollment: 110 Global Study Start Date: April 2015 Recruitment closed Q2/2016 Estimated Study Completion Date: November 2018 Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure) H TZH

41 T-VEC: Monotherapie-Studie (Study T-Vec ) Weltweit 45 Studienzentren 4 deutsche Studienzentren: Essen Frankfurt/Main Hannover Heidelberg 2 österreichische Studienzentren: Salzburg Wien 14 Patienten in Deutschland rekrutiert H TZH

42 Ipilimumab ± T-Vec in unresected melanoma (Study T-Vec ) H TZH

43 Ipilimumab ± T-Vec in unresected melanoma (Study T-Vec ) Global Study Start Date: February 2013 Estimated Study Completion Date: November 2017 Estimated Primary Completion Date: May 2016 (Final data collection date for primary outcome measure) Erste Ergebnisse am auf dem ESMO Kongress erwartet H TZH

44 Ipilimumab ± T-Vec in unresected melanoma (Study T-Vec ) Weltweit 40 Studienzentren 3 deutsche Studienzentren: Göttingen Kiel Tübingen 10 Patienten in Deutschland rekrutiert H TZH

45 Pembrolizumab +- T-VEC (Study T-Vec ) A Phase 1b/3, Multicenter, Open-label Trial of Talimogene Laherparepvec in Combination With Pembrolizumab (MK-3475) for Treatment of Unresected,Stage IIIB to IVM1c Melanoma (MASTERKEY-265) H TZH

46 Pembrolizumab +- T-VEC (Study T-Vec ) (abgeschlossen, nicht in D) H TZH

47 MASTERKEY-265 Phase 3 Study Design N = 660 N = 330 Unresectable stage III or IV melanoma Treatment naive Prior BRAFi allowed Injectable lesions R T-VEC Intralesional Pembrolizumab 200mg IV Q3W 1:1 T-VEC placebo Intralesional Pembrolizumab 200mg IV Q3W N = 330 Primary Endpoints: PFS and OS Long G V et SMR 2015 H TZH

48 Masterkey Zentren weltweit Studienzentren D Dresden Hannover Kiel Regensburg Tübingen Weitere in Planung Studienzentren CH Geneve Lausanne Zürich Studienzentren A Salzburg H TZH

49 T-VEC Ansprechpartner bei Amgen: Dr. med. Markus Schill Senior Medical Advisor Immuno-Oncology AMGEN GmbH Hanauer Str. 1, München Tel.: +49 (0) Fax: +49 (0) H TZH

50 Keynote 252-Studie A Phase 3 Study of Pembrolizumab + Epacadostat or Placebo in Subjects With Unresectable or Metastatic Melanoma Anderer Name: ECHO-301 (Epacadostat Clinical Development in Hematology and Oncology) H TZH

51 Keynote 252-Studie Epacadostat: IDO1-Inhibitor IDO1: Indoleamine 2,3 dioxygenase 1, metabolisiert Tryptophan H TZH

52 Best Overall Response by RECIST 1.1: Melanoma Efficacy Evaluable* Patients, n (%) Melanoma (n=19) 25 mg BID (n=2) 50 mg BID (n=12) 100 mg BID (n=4) 300 mg BID (n=1) ORR (CR+PR) 10 (53) 1 (50) 5 (42) 4 (100) 0 CR PR SD DCR (CR+PR+SD) 14 (74) 2 (100) 7 (58) 4 (100) 1 (100) PD 5 (26) 0 5 (42) 0 0 *By data cutoff for efficacy (October 1, 2015), patients had at least 1 postbaseline scan or discontinued or died before the first postbaseline scan. In patients who were treatment-naive for advanced/metastatic melanoma (n=16): ORR 56% DCR 75% Phase Ib-Studie: Hamid et al., SMR 2015 [Not approved] FOR MEDICAL INFORMATION PURPOSES ONLY. NOT FOR PROMOTIONAL USE. DO NOT COPY, DISTRIBUTE OR OTHERWISE REPRODUCE. 52

53 Best Overall Response by RECIST 1.1: Melanoma Efficacy Evaluable* Patients, n (%) Melanoma (n=19) 25 mg BID (n=2) 50 mg BID (n=12) 100 mg BID (n=4) 300 mg BID (n=1) ORR (CR+PR) 10 (53) 1 (50) 5 (42) 4 (100) 0 CR PR SD DCR (CR+PR+SD) 14 (74) 2 (100) 7 (58) 4 (100) 1 (100) PD 5 (26) 0 5 (42) 0 0 *By data cutoff for efficacy (October 1, 2015), patients had at least 1 postbaseline scan or discontinued or died before the first postbaseline scan. In patients who were treatment-naive for advanced/metastatic melanoma (n=16): ORR 56% DCR 75% Phase Ib-Studie: Hamid et al., SMR 2015 [Not approved] FOR MEDICAL INFORMATION PURPOSES ONLY. NOT FOR PROMOTIONAL USE. DO NOT COPY, DISTRIBUTE OR OTHERWISE REPRODUCE. 53

54 Keynote 252 Endpunkte Primär Progression-free survival (RECIST 1.1) Overall survival Sekundär Objective response rate (RECIST 1.1) Safety and tolerability H TZH

55 Keynote 252 Haupt-Einschlusskriterien Have histologically or cytologically confirmed melanoma Have unresectable Stage III or Stage IV melanoma A minimum of 1 measurable lesion by CT or MRI Provide a baseline tumor biopsy Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 H TZH

56 Keynote 252 Haupt-Ausschlusskriterien Prior systemic treatment (except BRAF directed therapy) Has received prior therapy with an anti-pd-1, anti-pd-l1, anti-pd-l2, anti-cd137, or IDO1 inhibitor or any other antibody or drug specifically targeting checkpoint pathways other than anti-ctla-4 which is permitted in the adjuvant setting H TZH

57 Keynote 252 Logistik 600 Patienten 112 Zentren weltweit Zentren D Zentren CH Buxtehude Geneve Essen Lausanne Hannover Zürich Kiel Tübingen H TZH

58 MSD Ansprechpartner Infocenter MSD 0800 / infocenter@msd.de H TZH

59 BoneMet Studie - Hintergrund ca. 25% der Melanompatienten haben Knochenmetastasen RankL-Antikörper Denosumab zugelassen bei Knochenmetastasen solider Tumore Immunologische Daten und klinische Kasuistiken legen synergistische Wirkung von Denosumab und Checkpoint-Inhibitoren nahe H TZH

60 BoneMet - Design Evaluation of immunological effects of the RANKL-inhibitor Denosumab when administered concurrently with PD1-blocking antibodies (Nivolumab, Pembrolizumab) in patients with metastatic malignant melanoma with bone involvement Einarmige Studie IIT Hannover/Essen H TZH

61 Primär BoneMet - Endpunkte Anzahl aktivierter T-Zellen im peripheren Blut Induktion von Interferon gamma im Plasma Sekundär Sicherheit Verträglichkeit Effektivität H TZH

62 20 Patienten 4 Zentren BoneMet - Logistik Sponsor: Hannover Clinical Trial Center LKP: Ralf Gutzmer, Hannover Translationale Untersuchungen: Jürgen Becker, Essen Beginn Rekrutierung: Q1/2017 H TZH

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64 Studientreffen ADO Dresden, Immunonkologische Studien, Melanom PD Dr. med. Patrick Terheyden, MA Stv. Klinikdirektor, Klinik für Dermatologie Leiter des Hautkrebszentrums Onkologisches Zentrum

65 6 WEEKS** 6 WEEKS** Phase IIIb/IV Checkmate 511 A Randomized, Double-blinded Phase IIIb/IV Study of Nivolumab 3 mg/kg plus Ipilimumab 1 mg/kg vs Nivolumab 1 mg/kg plus Ipilimumab 3 mg/kg in Treatment-naïve Subjects With Advanced Melanoma POPULATION TREATMENT Part 1 Double-blind ** Part 2 Open-label ENDPOINTS Eligible patients with unresectable stage III or IV melanoma (n=346) Treatment-naïve ECOG 0-1 Stratified by: PD-L1 expression* AJCC M stage R 1:1 Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg Q3W for 4 doses Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Q3W for 4 doses Nivolumab Flat Dose 480 mg Q4W (30 min infusion) Treat until progression*** OR unacceptable toxicity**** Primary endpoint: Incidence of drug-related grade 3-5 AEs # Secondary EPs: ORR # OS # & PFS # * PD-L1 positive: 5% tumor cell surface staining. Validated PD-L1 assay is used for stratification of patients and efficacy analyses. ** 6 weeks treatment-free period from last dose in part 1 to part 2 monotherapy flat dose. Treatment in Part 1 will no be revealed until the end of the study. *** Patients may be treated beyond initial RECIST v1.1-defined progression under protocol-defined circumstances and if considered by the investigator to be experiencing clinical benefit and tolerating the study drug. Such subjects must discontinue therapy when further progression is documented. **** Until disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends. # Fixed timepoint: After 6 months from the first dose of study treatment. (NCT ) Status September 2016 AEs = Adverse Events, EP = Endpoint, ORR = Objective Response Rate, OS = Overall Survival, PFS = Progression Free Survival

66 Phase IIIb/IV Checkmate 511 A Randomized, Double-blinded Phase IIIb/IV Study of Nivolumab 3 mg/kg plus Ipilimumab 1 mg/kg vs Nivolumab 1 mg/kg plus Ipilimumab 3 mg/kg in Treatment-naïve Subjects With Advanced Melanoma Brief Title: A Study of Two Different Dose Combinations of Nivolumab in Combination With Ipilimumab in Subjects With Previously Untreated, Unresectable or Metastatic Melanoma Brief Summary: The purpose of this study is to evaluate two different dose combinations of nivolumab and ipilimumab in the treatment of melanoma. Key Inclusion Criteria 1 : Subject must have been diagnosed with stage III or/and stage IV histologically confirmed melanoma [per American Joint Committee on Cancer (AJCC) staging system] that is unresectable or metastatic Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Subject has not been treated by systemic anticancer therapy for unresectable or metastatic melanoma Key Exclusion Criteria 1 : Subjects with active brain metastases or leptomeningeal metastases Subjects with ocular melanoma Subjects with active, known or suspected autoimmune disease Participants Germany: Essen, Heidelberg, Tübingen & München Global: 57 Sites Recruitment & Timelines: Estimated Enrollment: 346 Randomized to date in Germany: approx. 20 patients Estimated Primary Completion Date: May 2017 (final data collection date for primary outcome measure) Estimated Completion Date: April (NCT ) Status September For more information please visit

67 Phase IIIb/IV Checkmate 401 A Clinical Trial of Nivolumab Combined with Ipilimumab Followed by Nivolumab Alone as First Line Treatment of Patients With Histologically Confirmed Stage III (Unresectable) or Stage IV Melanoma POPULATION TREATMENT ENDPOINTS Eligible patients with unresectable stage III or IV melanoma (n=615) Treatment-naïve ECOG 0-2 Mucosal & ocular melanomas allowed No current disease spread to the brain Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Q3W for 4 doses THEN Nivolumab 3 mg/kg Q2W Treat until disease progression* OR unacceptable toxicity** Primary endpoint: Rate & frequency of grade 3-5 treatmentrelated, select AEs Secondary EPs: Incidence, mtto & mttr of all grade 3-4 select AEs # ORR, PFS & OS * Patients may be treated beyond initial RECIST v1.1-defined progression under protocol-defined circumstances and if considered by the investigator to be experiencing clinical benefit and tolerating the study drug. Such subjects must discontinue therapy when further progression is documented. ** Until disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends. # Including AE management and outcomes of AEs when managed according to the BMS management algorithms. (NCT ) Status September 2016 AEs = Adverse Events, EP = Endpoint, mtto = Median Time to Onset, mttr = Median Time to Resolution, ORR = Objective Response Rate, OS = Overall Survival, PFS = Progression Free Survival

68 Phase IIIb/IV CA A Clinical Trial of Nivolumab Combined with Ipilimumab Followed by Nivolumab Alone as First Line Treatment of Patients With Histologically Confirmed Stage III (Unresectable) or Stage IV Melanoma Brief Title: Nivolumab Combined With Ipilimumab Followed by Nivolumab Monotherapy as First-Line Treatment for Patients With Advanced Melanoma Brief Summary: The purpose of this study is to determine the effects of combination treatment of Nivolumab with Ipilimumab in patients with previously untreated advanced Melanoma. Key Inclusion Criteria 1 : Potential subjects must have advanced Melanoma (stage III or IV as confirmed by biopsy) with spread to other sites in the body and unable to be removed by surgery Potential subjects must be newly diagnosed with advanced Melanoma and received no treatment for the advanced disease. The subjects who received previous primary treatment and any additional treatment (which is given after the primary treatment) are permitted if it was completed at least 6 weeks prior to study entry and if the side effects of the treatment are resolved. If subjects received any of the following primary treatment previously; (they are not permitted to be enrolled in the study: anti-ctla-4, anti-pd-1, anti-pd-l1, anti-pd-l2, or any other drug specifically targeting T-cell costimulation or checkpoint pathways such as anti-cd-137. Potential subjects (with disease spread to brain) who previously received primary treatment are permitted if there was no evidence of disease as confirmed by the MRI (at least 2 weeks after the primary treatment is complete and with in 6 weeks of the first dose of the study drug). Potential subjects must not have received steroid treatment (>10 mg/day) for at least 2 weeks prior to study drug administration. (NCT ) Status September For more information please visit 68

69 Phase IIIb/IV CA A Clinical Trial of Nivolumab Combined with Ipilimumab Followed by Nivolumab Alone as First Line Treatment of Patients With Histologically Confirmed Stage III (Unresectable) or Stage IV Melanoma Brief Title: Nivolumab Combined With Ipilimumab Followed by Nivolumab Monotherapy as First-Line Treatment for Patients With Advanced Melanoma Brief Summary: The purpose of this study is to determine the effects of combination treatment of Nivolumab with Ipilimumab in patients with previously untreated advanced Melanoma. Key Exclusion Criteria 1 : There is no current (and not previously treated) disease spread to the brain Subjects who received prior therapy with an anti-ctla-4, anti-pd-1, anti PD-L1 or anti-pd-l2, anti-cd-137 agents (or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways) for adjuvant, neoadjuvant, or advanced melanoma treatment or as part of clinical trial Subjects with autoimmune disease. Subjects with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll All side effects from previous primary treatments other than alopecia, fatigue, or peripheral neuropathy must have resolved to Grade 1 or baseline before administration of study drug Participants Germany: 17 Sites: Hannover, Erlangen, Erfurt, Ludwigshafen, Kiel, Frankfurt, Berlin, Göttingen, Mainz, Dresden, Freiburg, Buxtehude, Schwerin, Leipzig, Lübeck, Mannheim, Würzburg Global: approx. 90 Sites Recruitment & Timelines: Estimated Enrollment: 615 Treated to date in Germany: approx. 16 patients Estimated Primary Completion Date: December 2021 (final data collection date for primary outcome measure) Estimated Completion Date: December (NCT ) Status September For more information please visit 69

70 Phase I/II CA A Phase I/II Dose Escalation and Cohort Expansion Study of the Safety and Tolerability of Urelumab in Combination With Nivolumab in Advanced/Metastatic Solid Tumors and B-cell Non-Hodgkins Lymphoma Part 1 Dose Escalation: Nivolumab plus Urelumab (CD137 / 4-1BB agonist) Part 2 Dose Expansion : Nivolumab Q2W plus Urelumab Q6W Main tumor Types: Melanoma (MEL), Non-small cell lung cancer (NSCLC), Squamous head and neck cancer (SCCHN), Diffuse-large B-Cell Lymphoma (DLBCL) Endpoints: 1 EP: Safety as measured by the rate of adverse events (AEs) and Serious Adverse Events (SAEs), is the primary endpoint of this Phase 1/2 study. All subjects who receive at least one (full or partial) dose of Urelumab or Nivolumab will be evaluated for safety during treatment and for up to 100 days in follow-up Key 2 EPs: Best Overall Response (BOR), Objective response rate (ORR), Duration of Response (DOR), Progression-free survival (PFS) rate (NCT ) Status September

71 Phase I/II CA A Phase I/II Dose Escalation and Cohort Expansion Study of the Safety and Tolerability of Urelumab in Combination With Nivolumab in Advanced/Metastatic Solid Tumors and B-cell Non-Hodgkins Lymphoma Brief Title: Study of the Safety and Tolerability of Urelumab Administered in Combination With Nivolumab in Solid Tumors and B-cell Non-Hodgkins Lymphoma Brief Summary: The purpose of this study is to determine which doses of Urelumab and Nivolumab are safe and tolerable when they are given together. Key Inclusion Criteria 1 : For Dose Escalation: Subjects with any previously treated advanced (metastatic or refractory) solid tumor type and B- cell non-hodgkin lymphoma For Cohort Expansion: Subjects must have a previously treated advanced solid tumor or B cell non-hodgkin's lymphoma to be eligible, ECOG performance status of 0 or 1 For certain subjects, willing and able to provide pre-treatment and on-treatment fresh tumor biopsy Women of child-bearing potential and men must use an acceptable method of contraception during treatment and for 23 weeks after treatment for women and 31 weeks for men Key Exclusion Criteria 1 : Known central nervous system metastases or central nervous system as the only source of disease Other concomitant malignancies (with some exceptions per protocol) Active, known or suspected autoimmune disease Uncontrolled or significant cardiovascular disease History of hepatitis (B or C) or history of active or latent tuberculosis (NCT ) Status September For more information please visit 71

72 Phase I/II CA A Phase I/II Dose Escalation and Cohort Expansion Study of the Safety and Tolerability of Urelumab in Combination With Nivolumab in Advanced/Metastatic Solid Tumors and B-cell Non-Hodgkins Lymphoma Brief Title: Study of the Safety and Tolerability of Urelumab Administered in Combination With Nivolumab in Solid Tumors and B-cell Non-Hodgkins Lymphoma Brief Summary: The purpose of this study is to determine which doses of Urelumab and Nivolumab are safe and tolerable when they are given together. Participants Germany: Essen Global: 12 sites Recruitment & Timelines: Estimated Enrollment: 240 Randomized to date in Germany: approx. 12 patients Estimated Primary Completion Date: December 2018 (final data collection date for primary outcome measure) Estimated Completion Date: September (NCT ) Status September 2016

73 University Hospital of Regensburg A prospective phase I and consecutive phase II, two-arm, randomized multi-center trial of temsirolimus in combination with pioglitazone, etoricoxib and metronomic low-dose trofosfamide versus dacarbazine (DTIC) in patients with advanced melanoma (Mel001 Study) Communicative reprogramming of metastatic melanoma in >= second-line therapy Albrecht Reichle, Sebastian Haferkamp Universität Regensburg Medizinische Klinik III, Dermatologie Regensburg, September 2016

74 Rationale Up-regulating tumor suppressor genes (e.g. PTEN) for modulating tumor behavior Normalizing homeostatic pathways, e.g. Wnt/β-catenin signaling Controlling melanoma-associated inflammation Targeting the late-stage overexpression of a nuclear transcription factor (PPARgamma) Epigenetic modelling with metronomic low-dose chemotherapy and transcriptional modulator Targeting the mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT/mTOR pathways, which are activated in most cutaneous and uveal melanomas

75 Metastatic melanoma (>= second-line): A randomized phase II trial Combined modularized therapy versus DTIC (Mel001) Treatment until progression or intolerable toxicity Temsirolimus 25 mg weekly Pioglitazone 60 mg p.o. daily (PPAR alpha/gamma agonist) Etoricoxib 60 mg p.o. daily (COX-2 inhibitor, PPAR beta antagonist) Trofosfamide 50 mg thrice daily The alterations in major components of the MAPK, such as BRAF and NRAS mutations, and mtor pathways, PTEN loss and AKT overexpression, seem to have substantial influence in melanoma progression

76 Primary objective Phase I: To determine the dose of temsirolimus to be used in phase II part of the study: 25 mg weekly Phase II (on-going): To determine objective response rate (ORR) Secondary objectives To evaluate overall survival (OS) To evaluate time to progression (TTP) To evaluate time to partial response (time to PR or better) (TPR) To evaluate quality of life To evaluate tolerability and safety

77 Key Inclusion Criteria Must be histologically diagnosed with metastatic melanoma or metastatic uveal melanoma and LDH level > 0.8 ULN Subjects may receive study medication as >= second-line therapy following immune therapy or failure of BRAF- and/or MEK targeting therapy independently of the BRAF mutation status Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 Documented brain metastases not allowed, unless the patient has completed successful local therapy for central nervous system metastases and has been off of corticosteroids for at least 4 weeks before enrollment.

78 Planned Study Timelines: Recruitment of patients is scheduled to December 2017 The minimum follow-up time from last patient recruited is 12 months

79 Teilnehmende Zentren 22 Patienten ausstehend Participating centers of the current randomized phase II trial: Further centers are wellcome!! Dermatology Magdeburg Dermatology, Homburg/Saar Dermatology, Nuremberg Dermatology, Mainz Dermatology, Rechts d. Isar Dermatology, Regensburg Hämatology/Oncology Regensburg

80 Investigator-initiated trial Sponsor: Universitätsklinikum Regensburg Finanzielle Unterstützung durch Pfizer Ansprechpartner: Prof. Dr. Albrecht Reichle: Tel.: PD Dr. Sebastian Haferkamp Tel.: Studienzentrale: Frau Montag Tel.:

81 Studientreffen ADO Dresden, Immunonkologische Studien, Melanom Diskussion Onkologisches Zentrum

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83 NRAS+; BRAF Wildtyp Katharina C. Kähler

84 Phase II Trial of Pimasertib Versus Dacarbazine in N- Ras Mutated Cutaneous Melanoma Eine multizentrische, unverblindete, randomisierte Prüfung der Phase II zu dem MEK-Hemmer Pimasertib oder Dacarbazin bei zuvor unbehandeltem Patienten mit lokal fortgeschrittenen oder metastastisch malignem, kutanem Melanom mit NRAS- Mutation Sponsor: Merck Serono

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90 Augsburg Berlin Bonn Buxtehude Düsseldorf Erlangen Essen Frankfurt am Main Hamburg Hannover Kiel Köln Leipzig Magdeburg Mainz München Münster Plauen Tübingen Würzburg

91 The primary objective to demonstrate a significant improvement of PFS in Pim treatment arm (investigator assessment) as compared to DTIC treatment arm was achieved (HR (95% CI): 0.59 (0.42,0.83); p= ), median PFS 13 weeks in Pim vs 6.9 weeks in DTIC treatment arm. A consistent trend was observed in favor of Pim treatment arm across imaging end points (PFS, ORR,DCR; per investigator and central read) and also considering prognostic factors. No substantial difference was noted in OS. The results of the OS analysis were confounded due to study design (cross-over allowed, 41/64 DTIC patients crossed over to Pim treatment).the safety profile of Pimasertib was consistent with previous studies and no new safety signals were identified. Daten werden beim diesjährigen ESMO Kongress präsentiert

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98 Ansprechpartner:Arra

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102 Zentren in Deutschland Essen Buxtehude Gera Heidelberg Homburg Ludwigshafen Lübeck München Hornheide

103 NIPAWILMA Studienstart: Jan 2015 (1. Zentrum geöffnet) FPI: Phase I abgeschlossen ermitteltes Dosislevel Nintedanib: 200mg BID Doppel-blinde Phase II ab KW34 gestartet Rekrutierungs-Übersicht Phase I: Site No. Offene Zentren 01 Essen 02 München 03 Heidelberg 04 Buxtehude Gera Münster/Hornheid e 07 Homburg 08 Ludwigshafen 09 Lübeck 10 UK Münster Offen seit Pat. gescree nt Erster Pat. gescreent Letzter Pat. gescreent Patienten randomisie rt Erster Pat. randomisie rt Letzter Pat. randomisie rt Sum: 24 10

104 Kontakt: Dirk Schadendorf, Prof. Dr ext 4342,

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108 PACMEL Studienstart: Okt 2014 (1. Zentrum geöffnet) FPI: Rekrutierungsende: Last Patient Last Visit: voraussichtlich 12/2016 Site No. offene Zentren 01 Essen 02 Tübingen 03 Köln 04 Erfurt 05 Kiel 06 Minden 07 Regensbur g Offen seit Pat. gescree nt letzter Pat. gescreent letzter Pat. gescreent Pat. randomisie rt erster Pat. randomisie rt letzter Pat. randomisie rt

109 Kontakt: Dirk Schadendorf, Prof. Dr ext 4342

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111 Targeted BRAF-Phase I/II- Studien Lisa Zimmer

112 Targeted BRAF-Phase I/II-Studien BOTTOM (IIT) Phase 2 LOGIC II CLGX818X2109 Phase 2 ImmunoCobiVEM (IIT) Phase 2 IMMU-TARGET (IIT) Phase 1/2 Folie L.Zimmer Titel Targeted BRAF-Phase II+III

113 BOTTOM Biopsy- and Biology-driven optimization of targeted therapy of metastatic melanoma (BOTTOM) in BRAF Inhibitor non-pretreated and pretreated subjects with advanced, non-resectable (Stage IIIC) or metastatic (stage IV) BRAFV600E/K mutation-positive melanoma Sponsor: Universitätsklinikum Essen, Prof. Dr. Dirk Schadendorf Folie L.Zimmer Titel Targeted BRAF-Phase II+III

114 BOTTOM Kohorte A Kohorte B Kohorte C Primärer Endpunkt: Korrelation des klinischen Ansprechens in Woche 8 mit molekularpathologischen Ergebnissen der Biopsien Sekundäre Endpunkte: ORR, DCR, PFS nach 6 Monaten, 1-Jahres OS, Safety Folie L.Zimmer Titel Targeted BRAF-Phase II+III

115 BOTTOM Haupteinschlusskriterien: BRAF V600E/K mutiertes kutanes Melanom St IIIC/IV, nicht resezierbar ECOG 0/1 Vorliegen einer biopsierbaren Läsion (darf keine RECIST-Läsion sein) Keine ZNS-Metastasen, außer: vorbehandelt (Stereotaxie, Chirurgie) und stabil 90 Tage, asymptomatisch, nicht steroidpflichtig, keine Antikonvulsiva, Zustimmung durch Sponsor erforderlich. Hauptausschlusskriterien: Okuläres Melanom oder Schleimhautmelanom Schwere kardiovaskuläre Vorerkrankungen Retinalvenenverschluß, zentrale seröse Retinopathie Folie L.Zimmer Titel Targeted BRAF-Phase II+III

116 BOTTOM Timelines: Rekrutierungsdauer: 15 Monate Einschluss erster Patient: Q Einschluss letzter Patient: Q Studienende: Q (= 1 Jahr nach 1. Therapiegabe des letzten Patienten) Folie L.Zimmer Titel Targeted BRAF-Phase II+III

117 BOTTOM- Rekrutierung Aktuelle Zahlen: LKP: Dirk Schadendorf Studienstart: Jul 2015 (1. Zentrum geöffnet) FPI: Stand , 7 Zentren in Deutschland geöffnet Folie L.Zimmer Titel Targeted BRAF-Phase II+III

118 BOTTOM Ansprechpartner UK Essen: Julia Grimm Mail: Phone: Ansprechpartner Alcedis: Dr. Joachim Stump Winchesterstr. 3 D Gießen Mail: jst@alcedis.de Phone: +49 (0) 641/ Folie L.Zimmer Titel Targeted BRAF-Phase II+III

119 BOTTOM - Studientreffen Folie L.Zimmer Titel Targeted BRAF-Phase II+III

120 LOGIC II CLGX818X2109 A phase II, multi-center, open-label study of sequential LGX818/MEK162 combination followed by a rational combination with targeted agents after progression, to overcome resistance in adult patients with locally advanced or metastatic BRAFV600 melanoma Sponsor: Array Folie L.Zimmer Titel Targeted BRAF-Phase II+III

121 LOGIC II CLGX818X2109 Primärer Endpunkt: ORR der Triple-Therapie nach Progress unter BRAFi/MEKi Sekundäre Endpunkte: Safety, Tolerability, PFS, DOR, TTR, DCR; nur Part II: OS, ORR; genomische Alterationen des Tumorgewebes, PK Folie L.Zimmer Titel Targeted BRAF-Phase II+III

122 LOGIC II CLGX818X2109 Haupteinschlusskriterien: BRAF V600 mutiertes Melanom St IIIC/IV, nicht resezierbar ECOG 2 Tumorgewebe verfügbar Hauptausschlusskriterien: Symptomatische ZNS-Metastasen, außer: asymptomatisch und stabil 4 Wochen, nicht steroidpflichtig oder stabile Steroiddosis über 4 Wochen. Schwere kardiovaskuläre Vorerkrankungen Retinalvenenverschluß, zentrale seröse Retinopathie Folie L.Zimmer Titel Targeted BRAF-Phase II+III

123 LOGIC II CLGX818X2109 Timelines: Einschluss erster Patient: Juli 2014 Einschluss letzter Patient: 9. November 2015 Voraussichtliches Studienende: 6. Januar 2017 Folie L.Zimmer Titel Targeted BRAF-Phase II+III

124 LOGIC II CLGX818X2109 Aktuelle Zahlen: Weltweite Rekrutierung, insgesamt 19 Zentren, davon 4 in Deutschland Würzburg (Anja Gesierich), Köln (Cornelia Mauch), Heidelberg (Jessica Hassel), München (Carlola Berking) Rekrutierung weltweit abgeschlossen: 157 Patienten Eingeschlossene Patienten in Deutschland: 37 Patienten Folie L.Zimmer Titel Targeted BRAF-Phase II+III

125 LOGIC II CLGX818X2109 Aktuelle Zahlen: Folie L.Zimmer Titel Targeted BRAF-Phase II+III

126 LOGIC II CLGX818X2109 Ansprechpartner: ARRAY und PPD Folie L.Zimmer Titel Targeted BRAF-Phase II+III

127 ImmunoCobiVem Phase II, multicenter, open-label, randomized-controlled Trial Evaluating the Efficacy and Safety of a Sequencing Schedule of Cobimetinib plus Vemurafenib followed by Immunotherapy with an anti- PD-L1 antibody Atezolizumab for the treatment in patients with unresectable or metastatic BRAF V600 mutant melanoma Sponsor: Universitätsklinikum Essen, Prof. Dr. Dirk Schadendorf Folie L.Zimmer Titel Targeted BRAF-Phase II+III

128 ImmunoCobiVem Primärer Endpunkt: Zeit bis PFS2 Sekundäre Endpunkte: Sicherheit, Toxizität, OS, 1-,2-Jahres OS, 1-,2-Jahres- DCR, PFS1, PFS3 Exploratorische Studienziele: Translationale Analyse Tumorgewebe/Blut; emars (electronic Medication Adherence Folie L.Zimmer Titel Targeted BRAF-Phase II+III Reminder System)

129 ImmunoCobiVem emars-konzept Run-In Phase (3 Monate = 12 Wochen) Dosis per Zyklus (4 Wochen): Vemurafenib (d1-d28): 960mg (4x240mg Tabletten) morgens und abends Cobimetinib (d1-d21): 60mg (3x20mg Tabletten) morgens Patient: kommt zur Visite in W3, W5, W7, W9 und Ende W12 Papier-Med.-Diary (Hauptstudie) Patient: führt Papier-Med.- Diary und bringt dieses zu Visiten mit Arzt: überprüft Med.-Diary bei Visite und pflegt dies ins ecrf ein Alcedis emars Patient: führt online Med.- Diary emars: erinnert Patient bei Nichteinnahme per SMS Arzt: überprüft Med.-Diary im ecrf bei Visite Ende der Run-In Phase: Patient: beantwortet Patienten-Fragebogen elektronisch Randomisation Phase Patienten können optional emars während Einnahme von Cobimetinib und Vemurafenib in Randomisation Phase weiter nutzen Pharmakovigilanz: Prüfen der Patienten- Einträge nach festgelegtem Schema Technischer Support: Telefon-Hotline und FAQ im ecrf Per Tablet am Zentrum Auswertung der Medikationsadhärenz nach 18 Monaten Studienlaufzeit Folie L.Zimmer Titel Targeted BRAF-Phase II+III

130 ImmunoCobiVem Haupteinschlusskriterien: BRAF V600 mutiertes kutanes Melanom St IIIB/IIIC/IV, nicht resezierbar Keine Vortherapie erlaubt ECOG 0/1, Tumorgewebe verfügbar Keine Hirnmetastasen außer, wenn behandelt (stereotaktisch oder chirurgisch) stabil 4 Wochen, asymptomatisch, nicht steroidpflichtig LVEF 50%, QTc 450 ms Hauptausschlusskriterien: Leptomeningeale Metastasen, Meningeosis carcinomatosa Immunsuppressive Therapie innerhalb von 7d vor Studienstart Schwere kardiovaskuläre Vorerkrankungen Retinalvenenverschluß, zentrale seröse Retinopathie Folie L.Zimmer Titel Targeted BRAF-Phase II+III

131 ImmunoCobiVem Timelines: Rekrutierungsdauer: 15 Monate Initiierung der ersten Zentren: ab Einschluss erster Patient: QIII 2016 Einschluss letzter Patient: QIV 2017 Dauer das Follow-up: 24 Monate nach Randomisierung des letzten Patienten Studienende: QI 2020 (= Last Patient Last Visit in der FU- Phase) Folie L.Zimmer Titel Targeted BRAF-Phase II+III

132 ImmunoCobiVem LKP: Dirk Schadendorf Europaweite Rekrutierung, insgesamt 30 Zentren, davon 20 in Deutschland Folie L.Zimmer Titel Targeted BRAF-Phase II+III

133 ImmunoCobiVem- 10 Zentren im Ausland Folie L.Zimmer Titel Targeted BRAF-Phase II+III

134 ImmunoCobiVem Ansprechpartner UK Essen: Julia Grimm: Mail: Phone: Ansprechpartner Alcedis: Dr. Joachim Stump Winchesterstr. 3 D Gießen Mail: jst@alcedis.de Phone: +49 (0) 641/ Folie L.Zimmer Titel Targeted BRAF-Phase II+III

135 ImmunoCobiVem - Studientreffen Folie L.Zimmer Titel Targeted BRAF-Phase II+III

136 IMMU-TARGET A randomized Phase I/II open label, multicentre study of encorafenib plus binimetinib and PD-1 antibody pembrolizumab in patients with unresectable or metastatic BRAF V600 mutant melanoma. Sponsor: Universitätsklinikum Essen, Prof. Dr. Dirk Schadendorf Folie L.Zimmer Titel Targeted BRAF-Phase II+III

137 IMMU-TARGET Studienaufbau Phase 1 Der Dosisfindung in Phase I liegt ein Dosisreduktions-Schema zugrunde: In jedem Schritt werden dafür 3 Patienten in die Studie eingeschlossen Dosis-limitierende Toxizitäten (DLT) werden nach 42 Tagen nach dem Start der Therapie (erste Pembrolizumab Gabe) bestimmt Folie Primäres 139 Studienziel: Sicherheit und Verträglichkeit L.Zimmer Titel Targeted BRAF-Phase II+III

138 IMMU-TARGET Studienaufbau Phase 2 Primärer Endpunkt: PFS, PFS-Rate nach 12,18, 24 Monaten Sekundärer Studienendpunkte: Sicherheit, ORR, Overall survival, OS- Rate nach 1- und 2-Jahren Folie L.Zimmer Titel Targeted BRAF-Phase II+III

139 IMMU-TARGET Haupteinschlusskriterien: BRAF V600 E oder K mutiertes Melanom St IIIB,IIIC/IV, nicht resezierbar Keine Vortherapie ECOG 0/1 Keine Hirnmetastasen außer, wenn behandelt, stabil 4 Wochen, asymptomatisch, nicht steroidpflichtig oder durchgängig Prednisolon <10mg erhalten Hauptausschlusskriterien: Leptomeningeale Metastasen, Meningeosis carcinomatosa Uvea-Melanom Schwere kardiovaskuläre Vorerkrankungen Retinalvenenverschluß, zentrale seröse Retinopathie Folie L.Zimmer Titel Targeted BRAF-Phase II+III

140 IMMU-TARGET Timelines: Studienstart (First Patient First Visit): Q Rekrutierungszeitraum 24 Monate Rekrutierungsende (Last Patient First Visit): Q Studienende (Last Patient Last Visit): Q Datenbankschluss Q Folie L.Zimmer Titel Targeted BRAF-Phase II+III

141 IMMU-TARGET LKP: Dirk Schadendorf 17 Zentren in Deutschland Folie L.Zimmer Titel Targeted BRAF-Phase II+III

142 IMMU-TARGET Ansprechpartner UK Essen: Julia Grimm: Mail: Phone: Ansprechpartner Alcedis: Dr. Joachim Stump Winchesterstr. 3 D Gießen Mail: jst@alcedis.de Phone: +49 (0) 641/ Folie L.Zimmer Titel Targeted BRAF-Phase II+III

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145 HautkrebsZENTRUM Rhein-Main Hautklinik und Poliklinik Impfstudien/Uveamelanom Carmen Loquai CL

146 HautkrebsZENTRUM Rhein-Main Hautklinik und Poliklinik Gliederung Impfstudie RP /Lipo-MERIT Studie Uveamelanomstudie FOCUS-PHP-OCM-301 Studie CL

147 HautkrebsZENTRUM Rhein-Main Hautklinik und Poliklinik RB_ : Lipo-MERIT Clinical first-in-human study dose escalation study evaluating the safety and tolerability of intravenous administration of a tetravalent RNA-lipoplex cancer vaccine targeting the tumorassociated antigens NY-ESO-1, tyrosinase, MAGE-A3, and TPTE in patients with advanced melanoma CL

148 HautkrebsZENTRUM mrna Vakzine für optimiertes DC-Targeting inhautklinik vivound Poliklinik Rhein-Main Local DC targeting MERIT (NCT ) IVAC MUTANOME (NCT ) Ultrasoundguided intranodal injection Thymus Tumor Systemic DC targeting Induction of combined innate and adaptive immunity Triggering of type I IFN network Strong therapeutic antitumor activity RNA RNA(LIP) Lymph node Intravenous injection Spleen Peyer s patch Bone marrow Excellent preclinical safety profile Strong therapeutic antitumor activity mrna and DCs meet directly at injection site TRON ggmbh Liposomal RNA vaccine targeting to DC Universally applicable for almost all types of tumor antigen Kranz, Diken et al, Nature 534, (June 2016) 150

149 HautkrebsZENTRUM Rhein-Main Hautklinik und Poliklinik RB_ : Lipo-MERIT Indikation: Malignes Melanom Stadium IIIB-IV Phase I-Studie, multizentrisch, open-label, nicht-randomisiert Teilnehmende Zentren: Mainz (LKP), Mannheim, Heidelberg, Frankfurt Anzahl der Patienten: (5-6 Kohorten) CL

150 HautkrebsZENTRUM Rhein-Main Hautklinik und Poliklinik RB_ : Lipo-MERIT Erster Patienteneinschluß: Letzter Patienteneinschluß: voraussichtlich Q Primäre Endpunkte: Sicherheit, Tolerabilität, Biologische Effekivität Sekundäre Endpunkte: Anprechen messbarer Tumorläsionen gemäß irrecist 1.1 Stand Sept. 2016: 8 eingeschlossene Patienten, 4 Patienten unter Behandlung CL

151 HautkrebsZENTRUM Rhein-Main Hautklinik und Poliklinik Gliederung Impfstudie RP /Lipo-MERIT Studie Uveamelanomstudie FOCUS-PHP-OCM-301 Studie CL

152 HautkrebsZENTRUM Rhein-Main Hautklinik und Poliklinik PHP-OCM-301-Studie: FOCUS A Randomized, Controlled, Phase 3 Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Melphalan/HDS Treatment in Patients with Hepatic-Dominant Ocular Melanoma CL

153 HautkrebsZENTRUM Rhein-Main Hautklinik und Poliklinik Studiendesign Melphalan/HDS* 3,0 mg/kgkg, bis zu 6x Uveamelanom, überwiegend hepatisch metastasiert *Hepatic Delivery System Randomisierung: 1:1 Kontrolle: DTIC, transarterielle Chemoembolisation (TACE), Ipilimumab, Pembrolizumab CL

154 HautkrebsZENTRUM Rhein-Main Hautklinik und Poliklinik Hepatic Delivery System (Delcath Device System) CL

155 HautkrebsZENTRUM Rhein-Main Hautklinik und Poliklinik Studiendesign Geplante Patientenzahl: 240 Anzahl der Zentren: 20 Zentren in Deutschland: 4 (Berlin, Marburg, Regensburg, Mainz) Primärer Endpunkt: Gesamtüberleben Sekundärer Endpunkt: Progressionsfreies Überleben, ORR Geöffnet zur Rekrutierung! CL

156 CL

157 Melanom-Hirnmetastasen Friedegund Meier, Dresden ADO - Studientreffen Dresden,

158 BRF / COMBI-MB A Phase II, Open-Label, Multicentre Study of Dabrafenib plus Trametinib in Subjects with BRAF Mutation- Positive Melanoma that has Metastasized to the Brain Sponsor: Novartis Clinicaltrials.gov: NCT

159 BRF117277/COMBI-MB: A Phase II, Open-Label, Multicentre Study of Dabrafenib plus Trametinib in Subjects with BRAF Mutation-Positive Melanoma that has Metastasized to the Brain Cohort A (N=75) V600E (centrally confirmed) Asymptomatic, ECOG 0-1 Without prior local therapy Cutaneous melanoma 2 systemic therapies 1 measurable brain lesion N = 120 Cohort B* (N=15) V600E (locally confirmed) Asymptomatic, ECOG 0-1 With prior local therapy Cohort C* (up to N=15) V600D/K/R (locally confirmed) Asymptomatic, ECOG 0-1 With or without prior local therapy Dabrafenib 150 mg BID + Trametinib 2 mg QD Cohort D* (N=15) V600D/E/K/R (locally confirmed) Symptomatic, ECOG 0-2 With or without prior local therapy *Rekrutierung beendet für Kohorten B-D Primary endpoint: Intracranial response (IR) Secondary endpoints: extracranial response (ER), overall response (OR), disease control (intracranial, extracranial, and overall), PFS, OS, and duration of all response. Clinicaltrials.gov: NCT

160 Ein- und Ausschlusskriterien Main inclusion criteria: Stage IV cutaneous melanoma (metastatic to the brain), and determined to be BRAF V600E/K/D/R mutation-positive Systemic naïve or received 2 previous systemic treatment regimens for metastatic melanoma. Prior systemic treatment in the adjuvant setting is allowed. Ipilimumab treatment must end at least 8 weeks prior to enrollment. Main exclusion criteria: -Subjects with ocular or mucosal melanoma -Neurological symptoms related to brain metastasis except for Cohort D where subjects can be symptomatic. -Prior treatment with a BRAF inhibitor or a MEK inhibitor. -Treatment with stereotactic radiosurgery within 14 days, or treatment with whole-brain radiation within 28 days prior to study treatment. Clinicaltrials.gov: NCT

161 Rekrutierung Aktueller Status (25. Aug. 2016): Enrolement closed 6 patients enrolled in 7 sites in Germany: C. Berking, München C. Garbe, Tübingen R. Gutzmer, Hannover J. Hassel, Heidelberg A. Hauschild, Kiel M. Kaatz, Gera C. Mauch, Köln Timelines: FPFV (global): 21. Feb 2014 FPFV (Germany)*: 04. Dec 2014 LPFV : 22 July st results to be ASCO 2017 (planned) * delayed participation of Germany due to BfS approval Clinicaltrials.gov: NCT ; data on file.

162 Ansprechpartner des Sponsors Kerstin Patzolt (project management) Phone Clinicaltrials.gov: NCT

163 CBKM120ZDE01T / BUMPER Buparlisib in Melanoma Patients Suffering From Brain Metastases Sponsor: Universitätsklinikum Tübingen Clinicaltrials.gov: NCT

164 An open-label, uncontrolled, single arm phase II trial of buparlisib in patients with metastatic melanoma with brain metastases not eligible for surgery or radiosurgery Melanoma brain metastases Asymptomatic, symptomatic ECOG 0-2 N = 22 BRAFwt failed prior immune checkpoint inhibitor BRAFV600 failed BRAFi Not eligible for surgery or radiosurgery Buparlisib 100 mg daily p.o. Primary endpoint: Intracranial disease control rate (IC-DCR; CR + PR + SD) assessed by investigators (modified RECIST 1.1) Secondary endpoints: ORR, duration of response, PFS, OS, safety Clinicaltrials.gov: NCT

165 Melanom-Hirnmetastasen: PI3K / AKT Inhibitoren - Rationale In Melanom-Hirnmetastasen ist der PI3K-AKT-Signalweg hyperaktiviert (Davies et al, Clin Cancer Res 2009; Meier et al, J Clin Oncol 30, 2012 (suppl; abstr 8526); Niessner et al, Cancer Medicie 2013; Chen G et al, Clin Cancer Res 2014) Der PI3K-Inhibitor Buparlisib hemmt das Wachstum von Melanomhirnmetastasenzellen in vitro und in vivo (Meier et al, J Clin Oncol 31, 2013 (suppl; abstr e20050); Chen G et al, Clin Cancer Res 2014; Niessner et al, Clin Cancer Res 2016) BRAFi PI3Ki MEKi

166 M13 Buparlisib M14 SHAM MRI days p.o. Der PI3K-Inhibitor Buparlisib hemmt das Wachstum von Melanom-Hirnmetastasen days p.o Niessner et al, Clin Cancer Res 2016

167 Ein- und Ausschlusskriterien Main inclusion criteria Histologically confirmed diagnosis of melanoma Pats. must have shown evidence for PD in the brain by MRI without leptomeningeal disease Pats. must not be eligible for surgery or radiosurgery Patients BRAF V600 wildtype: must have objective evidence of progressive disease during or following treatment with an immune checkpoint inhibitor Patients BRAF V600 mutation positive: must have objective evidence of progression of disease during or following treatment with a BRAF inhibitor Life expectancy > 8 weeks ECOG performance status < 2 Time interval between last day of previous anti-tumour local or systemic treatment and first dose of BKM120: 14 days elapsed from last treatment with surgery or radiosurgery 28 days elapsed from last treatment with whole brain radiation 28 days have elapsed from last dose of approved or investigational chemo-, cytokine-, immune-, biological-, or vaccine-therapy Clinicaltrials.gov: NCT

168 Ein- und Ausschlusskriterien Main exclusion criteria Leptomeningeal disease Requirement of >4 mg dexamethasone daily Participants with the following mood disorders as judged by the Investigator or a psychiatrist, or as result of participant s mood assessment questionnaire: history of or active major depressive episode bipolar disorder obsessive-compulsive disorder Schizophrenia suicidal attempt or ideation homicidal ideation CTCAE grade 3 anxiety Clinicaltrials.gov: NCT

169 Rekrutierung Aktueller Status (13. Sept. 2016) 9 patients enrolled 2 active sites in Germany Thomas Eigentler, Tübingen Claus Garbe, Tübingen Friedegund Meier, Dresden Timelines: Study Start Date: July 2015 (planned) October 2015 Estimated Study Completion Date: July 2018 Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure) Clinicaltrials.gov: NCT

170 Ansprechpartner PD Dr. Thomas Eigentler Phone Prof. Dr. Friedegund Meier Phone Clinicaltrials.gov: NCT

171 CA / BRAINIP trial BRAINIP An open label phase II study to evaluate safety and efficacy of combined treatment with ipilimumab and nivolumab in patients with four and more symptomatic brain metastases of melanoma Sponsor: Universitätsklinikum Tübingen

172 An open label phase II study to evaluate safety and efficacy of combined treatment with ipilimumab and nivolumab in patients with four and more symptomatic brain metastases of melanoma BRAINIP > 4 symptomatic melanoma brain metastases ECOG 0-2 Life expectancy >3 months N = 68 Without and with previous therapy Not eligible for surgery or radiosurgery NIVO 1mg/kg + IPI 3mg/kg Q3W for 4 doses then NIVO 3mg/kg Q2W Primary endpoint: Intracranial disease control rate (IC-DCR; CR + PR + SD) at 6 months of treatment assessed by investigators (RECIST 1.1 and irano) Secondary endpoints: mos, mpfs Percentage of pats in whom stereotactic irradiation or surgery of all metastases becomes applicable after PR Tolerability BORR at 6 months of treatment (RECIST 1.1) Cognitive function QoL

173 Ein- und Ausschlusskriterien BRAINIP Main inclusion criteria Presence of four or more active brain metastasis confirmed/evaluated by MRI Subjects with active brain metastases will be defined as subjects with brain metastases and any of the following focal neurological deficits, seizures, headache or any other neurological and/or psychiatric alteration that can be timely related to the diagnosis of CNS disease Subjects naïve for systemic treatment are eligible Subjects pre-treated with systemic immunotherapy, targeted therapy or chemotherapy, are eligible. Subjects with prior local therapy of brain metastases are eligible ECOG Performance Status 0, 1or 2 Expected life expectancy of more than three months

174 Ein- und Ausschlusskriterien Main exclusion criteria BRAINIP Ocular melanoma diagnosis Subjects, whose melanoma brain metastases were previously treated with systemic therapy with the combination of CTLA-4 and PD-1 antibodies, are not eligible. Active infection requiring systemic therapy Active, known or suspected autoimmune disease. Subjects with controlled Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger, are permitted to enroll. Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity. Patients should be excluded if they have positive test for hepatitis B virus surface antigen (HBs Ag) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

175 Rekrutierung BRAINIP Aktueller Status (13. Sept. 2016) 0 patients enrolled 15 sites in Germany (planned) Timelines: Study Start Date (FPFV) Date: October 2016 (planned) LPLV Date: September 2018 End of Study Date: September 2019 Clinicaltrials.gov: NCT

176 Ansprechpartner BRAINIP PD. Dr. Thomas Eigentler Phone Prof. Dr. Claus Garbe Phone Clinicaltrials.gov: NCT

177 ML30010 RadioCoBrim Dermatoonkologie F. Meier Radioonkoloogie E. Troost Neuroradiologie J. Linn Dresden Tübingen Heidelberg 179 Radiomics to identify MRI parameters that might be predictive of good response or side effects FPI Q (planned)

178 Melanom-Hirnmetastasen: BRAFi + MEKi - Rationale T T Increased PDGFRβ/IGF1R activity RAS mutation CRAF MEK mutation COT COT up-regulation RAS BRAF V600 MEK ERK Uncontrolled proliferation Spliced BRAF isoforms BRAFi MEKi Rationale Most common mechanism of acquired resistance to vemurafenib is MAPK reactivation through MEK 1,2 MEK + BRAF inhibition prevents the development of acquired resistance in preclinical models 3 MEK + BRAF inhibition (dabrafenib + trametinib 4 phase 3 and vemurafenib + cobimetinib phase 1/2) 5 improved response rates and PFS in BRAF inhibitor naive melanoma patients Reduced incidence of hyperproliferative lesions by blocking paradoxical activation of the MAPK pathway from RAF inhibition 6 Adapted with permission from AACR. 1 PFS, progression free survival. 1. Shi H et al. Cancer Discov. 2014;4: Trunzer K et al. J Clin Oncol. 2013;31: Paraiso K et al. Br J Cancer. 2010;102: Long GV et al. J Clin Oncol. 2014;32(5S): Ribas A et al. Lancet Oncol. 2014;15: Su F et al. New Engl J Med 2012;366:

179

180 Studientreffen ADO 2016 Therapiestudien bei kutanen Lymphomen Jan. P. Nicolay

181 Brentuximab Vedotin (C25001) A Phase 3 Trial of Brentuximab Vedotin(SGN- 35) Versus Physician's Choice (Methotrexate or Bexarotene) in Patients With CD30-Positive Cutaneous T-Cell Lymphoma Millennium Pharmaceuticals, Inc. / Seattle Genetics, Inc. Name I Folie 1 I Datum

182 Studienaufbau C25001 Phase III RCT Brentuximab-Vedotin i.v. alle 21 Tage versus Bexaroten mg/m² tgl. oder Methotrexat 5-50 mg p.o. wö. (physicians choice) bei PD im Kontrollarm crossover (SGN ) Name I Folie 1 I Datum

183 Wichtigste Ein- und Ausschlusskriterien Vorbehandelte (systemisch) Patienten >18 Jahre n = 124 Patienten CD30+ großzellig anaplastisches CTCL CD30+ MF (>10% der Zellen) CD30+ großzellig transformierte MF Name I Folie 1 I Datum

184 Brentuximab Vedotin (C25001) Zentren Berlin Kiel Krefeld Mannheim Mainz Minden Würzburg LKP: M. Weichenthal, Kiel Rekrutierungsstand: Deutschland: 6 weltweit: Studie komplett Name I Folie 1 I Datum

185 Pressemitteilung Alcanza C25001 ORR % im ADCETRIS-Arm versus 12.5 % im Bexa/MTX-Arm p < Alle sekundären Endpunkte inclusive Lebensqualität significant besser Präsentation ASH 12/2016 San Diego Name I Folie 1 I Datum

186 NCT Open-Label, Multi-Center, Randomized Study of Anti-CCR4 Monoclonal Antibody KW-0761 (Mogamulizumab) Versus Vorinostat in Subjects With Previously Treated Cutaneous T-Cell Lymphoma ( ) Sponsor: Kyowa Hakko Kirin Pharma, Inc. Name I Folie 1 I Datum

187 Studienaufbau KW Vorinostat 400 mg/d oral 317 Patienten Mogamulizumab 1mg/kg; d1,15 alle 4 Wochen Ende der Behandlungsphase nach 1 Jahr Nachbeobachtungsphase 36 Monate 317 Patienten, open-label, 1:1 randomisiert Endpunkte: PFS Response rate QoL Pruritus DoR Immunogenizität und Sicherheit von Mogamulizumab Name I Folie 1 I Datum

188 Wichtigste Ein- und Ausschlusskriterien Einschlusskriterien: Histologisch gesicherte Mycosis fungoides oder Sézary-Syndrom (CTCL Stadium Ib) bei Studieneinschluss ECOG 0-1 Vorbehandlung mit topischen oder systemischen CTCL-Therapien bis <28 Tage vor Studienbeginn (mind eine Vortherapie muss erfolgt sein) Ausschlusskriterien: Schwere Systemerkrankung oder Organdysfunktion Vortherapie mit Mogamulizumab oder Vorinostat Kontraindikation für eine Therapie mit Mogamulizumab oder Vorinostat Schwangere oder stillende Patientinnen, Patienten <18 Jahre Name I Folie 1 I Datum

189 Timelines Studienstart: 11/2012 Rekrutierungsende: 11/2015 Studienende: 2019 Geplante Datenveröffentlichung: 2019 Name I Folie 1 I Datum

190 Aktuelle Zahlen Teilnehmende Zentren: Weltweit 73 Zentren 2 Zentren in Deutschland: Mannheim Münster Rekrutierung komplett (373 Patienten) Name I Folie 1 I Datum

191 Ansprechpartner des Sponsors Name: Marietta Keckeis Telefonnummer: +49(0) Name I Folie 1 I Datum

192 NCT Phase IIA Study on Therapy With the NF-κB Inhibiting and Apoptosis Inducing Drug Dimethylfumarate (DMF) in Patients With Cutaneous T Cell Lymphoma (CTCL) (EudraCT-Number: ) IST-Sponsor: Medizinische Fakultät Mannheim/Heidelberg Name I Folie 1 I Datum

193 Studienaufbau CTCL DMF 25 Patienten, einarmiges Design Endpunkte: Reduktion des mswat Reduktion des Juckreizes DLQI Blutbeteiligung (bei St. IV) Name I Folie 1 I Datum

194 Wichtigste Ein- und Ausschlusskriterien Einschlusskriterien: Histologisch gesicherte Mycosis fungoides oder Sézary-Syndrom (CTCL Stadium Ib) bei Studieneinschluss mit therapieresistenter, progressiver Erkrankung oder Rezidiv Vorbehandlung mit topischen oder systemischen CTCL-Therapien bis <28 Tage vor Studienbeginn (mind eine Vortherapie muss erfolgt sein) Ausschlusskriterien: Weitere maligne Erkrankungen Vortherapie mit DMF oder gleichzeitige topische DMF-Behandlung Kontraindikation für eine Therapie mit DMF Schwangere oder stillende Patientinnen, Patienten <18 Jahre Name I Folie 1 I Datum

195 Timelines Studienstart: 02/2016 Studienende: Ende 2018 Geplante Datenveröffentlichung: September 2019/ADO-Tagung Name I Folie 1 I Datum

196 Aktuelle Zahlen Teilnehmende Zentren (Rekrutierungszahl): Mannheim (4/25) Kiel Krefeld (1/25) Ludwigshafen Minden (1/25) Würzburg Name I Folie 1 I Datum

197 Ansprechpartner des Sponsors LKP und Sponsorvertreter: Jan Nicolay Telefonnummer: Name I Folie 1 I Datum

198 A multicentre, double blind, randomised, placebo-controlled, Phase II trial to evaluate Resminostat for maintenance treatment of patients with advanced stage (Stage IIB-IVB) mycosis fungoides (MF) or Sézary Syndrome (SS) that have achieved disease control with systemic therapy the RESMAIN study Sponsor: 4SC AG, Martinsried Name I Folie 1 I Datum

199 Studienaufbau - RESMAIN 150 Patienten, doppel-blind, 1:1 randomisiert mit Placebokontrolle Endpunkte: PFS, Response rate, QoL, Pruritus, DoR, AEs Name I Folie 1 I Datum

200 Wichtigste Ein- und Ausschlusskriterien Einschlusskriterien: Histologisch gesicherte Mycosis fungoides oder Sézary-Syndrom (CTCL Stadium Ib gemäß der EORTC-ISCL Consensus-Klassifikation) bei Studieneinschluss mit CR; PR oder SD nach mind. einer Vortherapie Vorbehandlung mit systemischen CTCL-Therapien bis 2-8 Wochen vor Studienbeginn (mind eine Vortherapie muss erfolgt sein) Ausschlusskriterien: PD oder ZNS-Beteiligung des CTCL Schwere kardiale Vorerkrankung Kontraindikation für eine Therapie mit HDAC-Inhibitoren Schwangere oder stillende Patientinnen, Patienten <18 Jahre Name I Folie 1 I Datum

201 Timelines Studienstart: 10/2016 Rekrutierungsende: 12/2019 Studienende: noch nicht absehbar Geplante Datenveröffentlichung: noch nicht absehbar Name I Folie 1 I Datum

202 Aktuelle Zahlen Teilnehmende Zentren: Weltweit 50 Zentren in 10 Ländern geplant?? Zentren in Deutschland Rekrutierung noch nicht gestartet Name I Folie 1 I Datum

203 Ansprechpartner des Sponsors LKP: Prof. Rudolf Stadler Telefonnummer: +49 (0) Organisation: ICON; Melanie Milde Telefonnummer: +49 (0) Sponsor: 4SC, Martinsried; Dr. Daniel Vitt Telefonnummer: +49 (0) Name I Folie 1 I Datum

204

205 Merkellzellkarzinom

206 CA ADMEC Prospective randomized trial of an adjuvant therapy of completely resected Merkel Cell Carcinoma (MCC) with 3mg/kg BW Ipilimumab (Yervoy ) every 3 weeks for 12 weeks versus observation Universitätsklinik Essen BMS

207 ADMEC - Studienaufbau Geplante Patienten: 214 Gruppenzuteilung Arm A: Ipilimumab, 3 mg/kg KG Tag 1 (W1), 22 (W4), 43 (W7), 64 (W10). Arm B: Beobachtung Staging und Follow-up: Gemäß Leitlinien Endpunkte: DFS & OS

208 ADMEC Wichtigste Ein- und Ausschlusskriterien MCC Stage I III, no evidence of disease ECOG: 0 and 1 Adequate hematologic, liver and renal function

209 ADMEC Teilnehmende Zentren ADMEC Organisation Abteilung Nachname Vorname Universitätsklinikum Essen Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie Schadendorf Dirk Universitätshautklinik Tübingen Hautklinik Garbe Claus LMU München, Klinik und Poliklinik für Dermatologie und Allergologie Klinik und Poliklinik für Dermatologie und Allergologie Berking Carola Elbeklinikum Buxtehude Dermatologisches Zentrum Mohr Peter Universitätsklinikum Schleswig-Holstein Klinik für Dermatologie, Venerologie und Allergologie Kähler Katharina C. Universitätsklinik Carl Gustav Carus der Technischen Universität Dresden Nationales Centrum für Tumorerkrankungen Universitätsklinikum Heidelberg Dermatologie Meyer Friedegund Dermatologie Hassel Jessica Cecile Medizinische Hochschule Hannover Dermatologie Gutzmer Ralf Charité Dermatologie Kiecker Felix Gera Dermatologie Kaatz Martin Münster Hornheide Onkologie Fluck Michael

210 ADMEC - Aktueller Stand Studienstart: September 2014 Studienende: September 2017 Anzahl Patienten gescreent: 34 Anzahl Patienten randomisiert: 23 e no. City Country Open since Number of patients screened First patient screened Last patient screened Number of patients randomized First patient randomized Last patient randomized Essen Germany Buxtehude Germany Tübingen Germany Kiel Germany München Germany Dresden Germany Heidelberg Germany Berlin Germany Gera Germany Hannover Germany Münster Germany Summe 34 23

211 ADMEC - Aktueller Stand Studienstart: September 2014 Studienende: September 2017 Anzahl Patienten gescreent: 34 Anzahl Patienten randomisiert: 23 ADMEC Weiteres Vorgehen Verlängerung der Rekrutierungszeit Erweiterung der Zahl der Zentren auf 20 Fallweise Übernahme der Fahrtkosten

212 IMMOMEC A Phase II study of the tumour-targeting human F16IL2 monoclonal antibodycytokine fusion protein in combination with paclitaxel versus paclitaxel alone in patients with Merkel cell carcinoma Philogen European Commission

213 IMMOMEC - Aktueller Stand Studienstart: Oktober 2013 Rekrutierungsende: Juni 2016 Studienende: Dezember 2016 Anzahl Patienten gescreent: 41 Anzahl Patienten randomisiert: 21 Data Lock: Dezember 2016

214 JAVELIN MCC 200 A Phase II, open-label, multicenter trial to investigate the clinical activity and safety of MSB C (avelumab) in subjects with Merkel cell carcinoma EMD Serono

215 Anti-PD-L1 for advanced MCC Phase II, single arm of avelumab 10 mg/kg q2wks as second line therapy Multicenter US and Europe PI: Howard Kaufman, Rutgers University ClinicalTrials.gov identifier: NCT Activation PD-L1 PD-1 Tumor Cell Activated T Cell MHC TCR

216 Javelin MCC Rekrutierung below that I have to date, which includes a list of investigators/sites that have at least enrolled two patients in the study. It has not been fully verified so apologies in advance if it is not fully accurate but it may be helpful for you in collating a case study. UNITED STATES Russell, Jeffrey (Moffitt) 8 UNITED STATES Kaufman, Howard 7 UNITED STATES Hamid, Omid 7 UNITED STATES Bhatia, Shailender 7 GERMANY Terheyden, Patrick 5 UNITED STATES D'Angelo, Sandra (MSKCC) 5 UNITED STATES Shih, Kent (Tenn) 4 FRANCE Lebbe, Celeste 3 UNITED STATES Linette, Gerald (Wash) 3 ITALY Milella, Michele 3 UNITED STATES Brownell, Isaac (NCI) 3 UNITED STATES Lewis, Karl (CO) 3 ITALY Buzzoni, Roberto 2 FRANCE Robert, Caroline 2 UNITED STATES Ferrarotto, Renata (MDA) 2 AUSTRALIA Hill, Andrew 2 FRANCE Mortier, Laurent 2 ITALY Ascierto, Paolo 2 JAPAN Yamazaki, Naoyo (NCI) 2

217

218 Reponses to Avelumab

219 Javelin MCC st Line Extension Phase II, single arm of avelumab 10 mg/kg q2wks as first line therapy Multicenter US and Europe PI: Howard Kaufman, Rutgers University ClinicalTrials.gov identifier: NCT Currently open European sites: Activation PD-L1 PD-1 Tumor Cell Activated T Cell MHC TCR

220 Anti PD-1 for advanced MCC Multicenter, Phase II, single arm of pembrolizumab, 2mg/kg q3wks as first line therapy PI: Paul Nghiem and the Cancer Immunotherapy Trials Network (CITN), CTEP ClinicalTrials.gov Identifier: NCT Activation PD-L1 PD-1 Tumor Cell Activated T Cell MHC TCR

221

222 Responses are Independent of Viral or PD-L1 Status

223 BMS CA (Nivo) Non-Comparative, Two-Cohort, Single Arm, Open-Label, Phase 1/2 Study of Nivolumab (BMS ) in Subjects with Virus-positive Solid Tumors ClinicalTrials.gov - NCT Cohort A (Biopsy / Neoadjuvant): 84 subjects prior to surgery Cohort B (Metastatic): 115 subjects with recurrent or metastatic disease who have had one prior line of therapy for recurrent or metastatic disease

224 BMS CA (Nivo) Safety and tolerability of neoadjuvant nivolumab in patients with resectable tumors: HPV-positive SCCHN, EBV related gastric cancer, Merkel Cell Carcinoma, HPV positive cervical/vulvar cancers Investigator-assessed objective response rate (ORR) of nivolumab: EBV-related Nasopharyngeal or Gastric carcinoma, Merkel Cell Carcinoma, HPV positive cervical/vulvar cancers, HPV positive Squamous Cell cancer of the Head and Neck (SCCHN) Active Centers in Germany University Hospital Essen; Site 0027; Contact: Dirk Schadendorf, Site Klinikum Am Gesundbrunnen Heilbronn; Site 0028; Contact: Uwe Martens

225 M etastatic Biopsy/NeoAdjuvant SYNOPSIS REVIEW PACKAGE (THIS DOCUMENT IS INTENDED FOR INTERNAL USE ONLY AND IS NOT TO BE DISTRIBUTED EXTERNALLY) BMS CA (Nivo) Screening Treatment Subsequent Treatment Follow-Up Up to 4 weeks Tumor Types EBV Gastric HPV SCCHN HPV GYN (cervical/vulvar) M CC N=16 with Virus + for each tumor type N=5 with Virus for each tumor type except MCC Biopsy (Prior to 1st dose) Nivo M onotherapy 3mg/kg x 2 doses ORR Biopsy or Surgical Resection (Day 28) 10 subjects S afety analysis Addtional 6 subjects if 2 /10 h av e surgery delayed > 6 weeks due to AE Treatment Options Standard of Care or Nivolumab 3 mg/kg IV q14 days until toxicity or progression if medically eligible (i.e. meet criteria for metastatic cohort) M in 12 weeks Survival M ax 3 years 1 prior treatment for m etastatic disease 1 target lesion ECOG PS: 0-1 Tumor Types EBV NPC EBV Gastric HPV SCCHN M CC HPV GYN (cervical/vulvar) Nivo M onotherapy 3mg/kg Q2wk Until toxicity or progression On-Treatment Assessment Imaging every 6 weeks starting at week 6 for the first year of treatment. Imaging every 12 weeks starting at year 2 and beyond M in 12 weeks N=23 for each tumor type

226 MCC-Register online Merkelzellkarzinomregister der ADO finanzielle Unterstützung: keine

227 MCC-Register: Studienaufbau Versorgungsforschung prospektive und retrospektive Erfassung Tumordaten Therapie Verlauf aktuell: 1036 Erstmeldungen, 479 mit F/U Zukünftig: Histologische Zweitbegutachtung und zusätzliche prognostische Marker

228

229 ZDO Zentrum für Dermatoonkologie Universitäts-Hautklinik Tübingen PD Dr. med. Ulrike Leiter Neue Studie beim epithelialen Tumoren Ulrike Leiter Centre of Dermato-Oncology University of Tuebingen, Germany

230 Plattenepithelkarzinom A Phase II Study of REGN 28010, a Fully Human Monoclonal Antibody to PD-1 in Patients with Advances Cutaneous Squamous cell carcinoma 2 Gruppen Group 1 Patients with metastatic CSCC: to distant sites or lymph nodes Group 2 Patients with unresectable locally advanced CSCC Drug: REGN2810 Drug: REGN2810

231 Plattenepithelkarzinom Primary Outcome Measures: Overall Response Rate During 12 treatment cycles (96 weeks) Overall Response Rate as determined by RECIST 1.1 for Group 1 and/or assessed per composite response criteria (Group 2) Secondary Outcome Measures: Duration of response PFS Overall Survival Change in scores of patient reported outcomes on EORTC QLQ- C30

232 Plattenepithelkarzinom Key Inclusion Criteria: >18 years of age At least 1 measurable lesion (ECOG) performance status 1 Adequate bone marrow function Adequate renal function Adequate hepatic function Archived or newly obtained tumor material Patients must consent to undergo biopsies of externally visible CSCC lesions (Group 2 only) Surgical or radiological treatment of lesions contraindicated

233 Plattenepithelkarzinom Key Exclusion Criteria: Autoimmune disease, ongoing or recent ( 5 years) that required treatment with systemic immunosuppressive treatments Prior treatment with an agent that blocks the PD-1/PD- L1pathway Prior treatment with a BRAF inhibitor Prior treatment with other immune modulating like CTLA-4, 4-1BB (CD137), or OX-40. Untreated brain metastasis (considered as active) Immunosuppressive corticosteroid doses (>10 mg prednisone /d) within 4 weeks prior to the first dose of REGN2810 HIV and/or chronic/active infection Hepatitis B or C virus

234 Plattenepithelkarzinom Key Exclusion Criteria: History of pneumonitis within the last 5 years Allergic reactions attributed to antibody treatments Known allergy to doxycycline or tetracycline Patients with a history of solid organ transplant Any medical co-morbidity, physical examination finding, or metabolic dysfunction, or clinical laboratory abnormality that renders the patient unsuitable Other protocol-defined inclusion/exclusion criteria may apply

235 Plattenepithelkarzinom Ansprechpartner : Prof. Hauschild, Kiel Estimated Enrollment: 129 Study Start Date: March 2016 jetzt Herbst 2016 Estimated Study Completion Date: May 2019 Estimated Primary Completion Date: May 2019

236 Plattenepithelkarzinom Studienstart Herbst 2016 Teilnehmende Zentren: Essen Kiel Frankfurt Berlin Charité Dresden Hannover Tübingen

237 Weitere Studien mit dieser Substanz der Firma Regeneron sind für das Merkelzellkarzinom Basalzellkarzinom im nächsten Jahr geplant. Europ. PI: Prof. Hauschild, Kiel bei Fragen gerne kontaktieren

238 Basalzellkarzinom 1. Non-Interventional study to investigate the effectiveness, Safety and utilization of Vismodegib on locally advanced and symptomatic metastastic basal cell carcinoma under real world CONDITIONS (NIELS) Patienten, die bis ihre 1. Gabe Vismodegib erhalten haben, können hier noch eingeschlossen werden 2. Vismodegib on Locally Advanced and Metastatic Basal Cell Carcinoma Under Real World Conditions (JONAS) Folgeprojekt Sponsor: University Hospital, Essen Collaborator: OnkoDataMed GmbH

239 Basalzellkarzinom Teilnehmende Zentren: Alle am ADOREG teilnehmenden Zentren Estimated Enrollment: 53 Study Start Date: May 2016 Estimated Study Completion Date: April 2020 Estimated Primary Completion Date: April 2020

240 Basalzellkarzinom JONAS Primary Outcome Measures: duration of response (partial or complete) until progression, death or up to 3 years from first dose Vismodegib Secondary Outcome Measures: objective response rate, time to response, disease control rate, recurrence rate, time to progression, survival

241 Basalzellkarzinom Inclusion Criteria: Willing and able to provide informed consent Age 18 years labcc (inappropriate for surgery or radiotherapy) mbcc (histologic confirmation of distant BCC metastasis) (including symptoms of metastases e.g. pain, fatigue, disturbed sleep, lack of appetite, nausea/vomiting, shortness of breath, disturbed remembering, dry mouth and coughing will be documented) Patient is not included in any other trial Male or female patient is included in the pregnancy prevention program, as determined by the German authority (BfArM)

242 Basalzellkarzinom Exclusion Criteria: Patients, for whom treatment with Vismodegib is contraindicated according to the Summary of Product Characteristics (SmPC), which has been in effect at the time of treatment with Vismodegib, including: Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. of the latest SmPC Women who are pregnant or breast-feeding Women of childbearing potential who do not comply with the Vismodegib (Erivedge) Pregnancy Prevention Programme Coadministration of St John's wort (Hypericum perforatum)

243 Basalzellkarzinom A PHASE II, SINGLE-ARMED, MULTICENTER TRIAL OF NEOADJUVANT VISMODEGIB IN PATIENTS WITH LARGE AND/OR RECURRENT BASAL CELL CARCINOMA NICCI

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245 NICCI A PHASE II, SINGLE-ARMED, MULTICENTER TRIAL OF NEOADJUVANT VISMODEGIB IN PATIENTS WITH LARGE AND/OR RECURRENT RESECTABLE BASAL CELL CARCINOMA Martin Kaatz SRH Wald-Klinikum Gera GmbH Straße des Friedens 122 D Gera 247

246 Studienaufbau Geplante Patientenanzahl: 65 Patienten Gruppenzuteilung: keine/ nicht randomisiert Therapieschema: 3 Zyklen a 28 Tage mit 150mg Vismodegib Primäre Endpunkte: Bewertung der Krankheitskontroll-Rate (DCR) Auswertung der objektiven und relativen (%) Reduktion der betroffenen Hautoberfläche 248

247 Studienaufbau 249

248 Wichtigste Einschlusskriterien - Patient hat wenigstens ein großes BCC: 2 cm im Durchmesser im Kopf-/Hals-Bereich oder 5 cm an Rumpf/Extremitäten - Histologisch gesicherter Befund - Optional: Durchführung von nichtinvasiven bildgebenden Untersuchungen mittels konfokaler Laserscanmikroskopie (CLSM) und/oder optischer Kohärenztomographie (OCT) während und nach Beendigung der Studienbehandlung 250

249 251

250 Wichtigste Ausschlusskriterien - maximal eine Radiotherapie der Zielläsion(en) erlaubt, (mindestens 6 Monate vor Registrierung abgeschlossen) - Vorbehandlung mit einem Hedgehog-Inhibitor - Metastasiertes Basalzellkarzinom - Metatypisches Basalzellkarzinom - Bekanntes oder vermutetes Gorlin-Goltz-Syndrom 252

251 Timelines Einreichung: Einschluss des ersten Patienten (FPI): Q4 / 2016 Einschluss des letzten Patienten (LPI): Q4 / 2017 Ende der Behandlung (LP off treatment): Q1 / 2018 Ende der Nachbeobachtung (LP off study): Q1 /

252 10 Prüfzentren SRH Wald-Klinikum Gera GmbH Universitätsklinikum Tübingen Charité - Universitätsmedizin Berlin Elbe Kliniken Stade - Buxtehude GmbH Klinikum Augsburg Süd Klinikum Nürnberg Nord Universitätsklinikum Heidelberg Universitätsmedizin Rostock Universitätsklinikum Münster Fachklinik Hornheide 254

253 Ansprechpartner LKP: PD Dr. med. habil. Martin Kaatz Medical: Sabine Sell, OÄ Beatrice Schell, Julia Feld PM, IMP: Dr. Claudia Deumer OCT, CLSM: Dr. Michael Zieger Zentral erreichbar über: Tel.: +49 (0) 365 /

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255 ADOREG Aufbau und Betrieb eines prospektiven Registers zur Versorgungsforschung in der dermatologischen Onkologie Arbeitsgemeinschaft Dermatologische Onkologie

256 berichtet ADOREG -- Steuerung, Lenkung sowie Beteiligung (Stand 06/2015) Wiss. Beirat DKG DDG ADO Katalinic Enk Grabbe beaufsichtigt berichtet Leitungsgruppe Garbe, Reimer,. Schadendorf, Hansen, Weichenthal Berät Schlägt vor Pharmazeutische Projektgruppe Almirall Amgen, BMS, Leo, Medac, Novartis, Roche formuliert Anforderungen berät Trustcenter Hochschule Heilbronn Zentren Projektleitung Basissoftware Leiter, Hansen, Plötner, Weichenthal formuliert Anforderungen berät/ betreut A B C D E F G H N Akademischer Projektbeirat Ugurel, Augustin, Berking, Gutzmer, Weichenthal Definiert Studien, ernennt Leitung Leitung Projekt 1 Leitung Projekt 2 Leitung Projekt n

257 ADOREG-Datenschutzkonzept

258 ADOREG-Zentrenstatus 40 aktive Zentren 8 weitere Verträge in Verhandlung bzw. in Zeichnungsumlauf Interesse österreichischer Kliniken

259 Status Patienteneinschlüsse 09/2016 Entität Anzahl Patienten MM BCC 133 Gesamtzahl Patienten 1.632

260 ADOReg Rekrutierung

261 ADOReg Melanomfälle Klinisches Stadium Anzahl Patienten 0 9 IA 12 IB 18 II 3 IIA 32 IIB 60 IIC 48 III 7 IIIA 80 IIIB 154 IIIC 166 IV 854

262 Status Teilregister epitheliale Tumoren BCC-Register fertig programmiert und getestet, aktuell 133 Fälle Freischaltung für die Zentren seit Oktober 2015 Aktuell: Planung SCC-Register Vorplanungen MCC-Register Vorbereitung AK-Register

263 ADOReg NIS meets Register ADO-Reg Combi-R PEM Now

264 PemNow

265 PemNow Studienleiter: Dr. Peter Mohr, Buxtehude Geplante Patienten: 400 Einschluss: nach unter Behandlung mit Pembrolizumab EAP oder nach Zulassung Gesonderte Honorierung zusätzlich zur ADOReg-Basishonorierung Kontakt:

266 PemNow 08/2016 Eingeschlossene Patienten: 405 Geplante Aufstockung auf 550 Patienten Budget für Dokumentation in Verhandlung Rekrutierung on hold Anzahl teilnehmender (aktiver) Zentren Anzahl eingeschlosse ner Patienten Anzahl vollständiger Patienten

267 COMBI-r, eine nicht-interventionelle Studie bei Patienten mit fortgeschrittenem Melanom zur Bewertung der Kombinationstherapie mit Dabrafenib und Trametinib in der klinischen Routine (DRB436BDE04) Sponsor: Novartis BfArM: Nr Juli 2016

268 COMBI-r Kombinationstherapie Dabrafenib+Trametinib in der klinischen Routine Dokumentationszeitraum 12/ /2019 Wichtigste Ziele Effizienz & klinischer Nutzen Sicherheit & Verträglichkeit Lebensqualität (QoL) Korrelation Biomarker & klinischer Parameter mit klinischem Nutzen Therapie-Sequenz vor/nach Therapie Dauer der Therapie & Therapie- Management Methoden der BRAFV600- Mutationsanalyse BfArM: Nr. 6690

269 COMBI-r Kombinationstherapie Dabrafenib+Trametinib in der klinischen Routine Patientendaten, die in COMBI-r dokumentiert wurden, können in das ADOREG Register überführt werden und so zusätzlich einer unabhängigen Auswertung und Nutzung durch die ADO zur Verfügung stehen. Datentransfer ins ADOREG nach ausdrücklicher und individueller Zustimmung des Patienten ADOREG BfArM: Nr. 6690

270 COMBI-r Kombinationstherapie Dabrafenib+Trametinib in der klinischen Routine Aktuelle Zahlen Teilnehmende Zentren: 48 (Stand August 2015) bis zu 60 Zentren geplant Dokumentierte Patienten: 68 (Stand August 2016)

271 Ansprechpartner Clinical Research Manager (Projektmanagement und wissenschaftliche Fragen): Antonia Wolff Medical Advisor (wissenschaftliche Fragen): Dr. Julia Kleylein-Sohn

272 JONAS Nicht-interventionelle Studie zur Untersuchung der Wirksamkeit, Sicherheit und Anwendung von Vismodegib bei lokal fortgeschrittenem und metastasierten Basalzellkarzinom unter realen Bedingungen

273 berichtet ADOREG -- Steuerung, Lenkung sowie Beteiligung (Stand 06/2015) Wiss. Beirat DKG DDG ADO Katalinic Enk Grabbe beaufsichtigt berichtet Leitungsgruppe Garbe, Reimer,. Schadendorf, Stiegler, Weichenthal Berät Schlägt vor Pharmazeutische Projektgruppe Almirall Amgen, BMS, Leo, Medac, Novartis, Roche formuliert Anforderungen berät Trustcenter Hochschule Heilbronn Zentren Projektleitung Basissoftware Leiter, Stiegler, Thielecke, Weichenthal formuliert Anforderungen berät/ betreut A B C D E F G H N Akademischer Projektbeirat Augustin, Berking, Gutzmer, Ugurel, Weichenthal Definiert Studien, ernennt Leitung Leitung Projekt 1 Leitung Projekt 2 Leitung Projekt n

274 Zielsetzung Akademische Projekte in ADOREG Projekte / Studien mit akademischer Fragestellung innerhalb des Registers ADOREG prospektiv und/oder retrospektiv Aktuelles akademisches ADOREG Projekt: TRIM (prospektiv) Weitere Projekte geplant nach Antragseinreichung und Beurteilung durch den akademischen Projektbeirat Akademischer Projektbeirat 5 Mitglieder: Selma Ugurel (Essen) Carola Berking (München), Ralf Gutzmer (Hannover), Matthias Augustin (HH), Michael Weichenthal (Kiel) Ablauf Einreichung einer Antragsskizze Beurteilung der Realisierbarkeit und Finanzierung (vor allem bei prospektiven Projekten) Erste Anträge zunächst aus den ADO Kommittees geplant (CIE Translationale Forschung; CIE Nebenwirkungen, CIE Supportivtherapie)

275 TRIM (Tissue Registry in Melanoma) Akademisches Projekt in ADOREG Projektleiter: Dirk Schadendorf, Selma Ugurel (Essen) Ziele des Projektes multizentrische Sammlung von Daten zur molekularen Charakterisierung von Tumorgewebe bei Patienten mit metastasiertem Melanom vor Einleitung einer systemischen Therapie Untersuchung der molekularen Parameter als prädiktive / prognostische Marker Einschlusskriterien Patienten mit metastasiertem Melanom im Stadium III oder IV Geplante systemische Therapie in jeglicher Therapielinie Tumorgewebe des Patienten als Paraffinmaterial vorhanden (möglichst aktuelles Probenmaterial aus Metastase; älteres Gewebematerial bis hin zum Primärtumor auch möglich) Einwilligung des Patienten in Projektteilnahme TRIM und Datenerfassung über ADOREG

276 TRIM (Tissue Registry in Melanoma) Durchführung Registrierung des Patienten über ADOREG Versand von Tumorgewebe in Form von Paraffinblock oder Schnittpräparaten (20 Stück) an Labor der Hautklinik Essen Untersuchung der Gewebe auf Mutationen in 30 Melanom-relevanten Genen mittels Next-Generation- Sequencing (MiSeq, Illumina) PD-L1 Expression mittels Immunhistochemie (PharmDx 28-8 auf DAKO Autostainer) Nach 7-14 Tagen Erhalt eines Ergebnisbefundes über ADOREG Finanzierung Materialkosten übernommen von BMS Molekulare Analysen für das Zentrum kostenfrei Im Gegenzug Dokumentation der klinischen Daten (Baseline und FollowUp) in ADOREG durch das Zentrum ohne zusätzliche Vergütung Basis-Dokumentation der betreffenden Patienten regulär vergütet über ADOREG

277 TRIM (Tissue Registry in Melanoma) Stand vom : Aktive Zentren: 12 Eingeschlossene Patienten: 332 Anzahl der eingesandten Gewebeproben: 364 Kontakt:

278 TRIM (Tissue Registry in Melanoma) Auswertung Korrelation der Daten aus molekularer Diagnostik mit dem klinischen Verlauf der Patienten: prädiktive Aussage bezüglich Therapieansprechen und Überleben? Vergleich mit bekannten prognostischen und prädiktiven Markern des Melanoms Anmeldung zum Projekt / Ansprechpartner über ADOREG über Universitäts-Hautklinik Essen: LABOR: Antje Sucker (antje.sucker@uk-essen.de) DATENBANK: Selma Ugurel (selma.ugurel@uk-essen.de)

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