ZDO
ADO-StudientreffenMelanom – Adjuvant/Neoadjuvant
Thomas EigentlerDresden, 22.09.2016
ZDO
Stadium II
ZDO
EORTC-18081Adjuvant Pegylated-Interferon-alpha2b (SylatronTM) for 2 Years Versus
Observation in Patients With an Ulcerated Primary Cutaneous Melanoma WithT(2-4)bN0M0: a Randomized Phase III Trial of the EORTC Melanoma Group
• Patienten mit ulzerierten Primärmelanomen habeneine ungünstigere Prognose (AJCC 2010)
• In Vorstudien haben Patienten mit ulzeriertenPrimärmelanomen in Subgruppenanalysen besondersvon einer ajduvanten Therapie profitiert
ZDO
EORTC-18991PEG-Intron Observation After Regional Lymph Node Dissection in AJCC Stage
III (TxN1-2M0) Melanoma Patients: a Randomized Phase III Trial
* Nur Patienten mit Mikrometastasen im SN
ZDO
Firstline
Patients with an
ulcerated
melanoma with
Breslow >1 mm,
N0M0
• 1200 patients
• stages IB-IIC
tumor-free
R
A
N
D
O
M
I
Z
A
T
I
O
N
ARM A
Biological: PEG IFN
alfa-2b 3µg/kg weekly
injections for 2 y.
ARM B
No Intervention:
Observation
1:1
EORTC-18991PEG-Intron Observation After Regional Lymph Node Dissection in AJCC Stage
III (TxN1-2MO) Melanoma Patients: a Randomized Phase III Trial
ZDO
EORTC-18081Adjuvant Pegylated-Interferon-alpha2b (SylatronTM) for 2 Years Versus
Observation in Patients With an Ulcerated Primary Cutaneous Melanoma WithT(2-4)bN0M0: a Randomized Phase III Trial of the EORTC Melanoma Group
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]
ZDO
EORTC-18081Adjuvant Pegylated-Interferon-alpha2b (Sylatron TM) for 2 Years Versus
Observation in Patients With an Ulcerated Primary Cutaneous Melanoma WithT(2-4)bN0M0: a Randomized Phase III Trial of the EORTC Melanoma Group
Inclusion Criteria:
• Subjects must be between 18-70 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)
ZDO
EORTC-18081Adjuvant Pegylated-Interferon-alpha2b (Sylatron TM) for 2 Years Versus
Observation in Patients With an Ulcerated Primary Cutaneous Melanoma WithT(2-4)bN0M0: a Randomized Phase III Trial of the EORTC Melanoma Group
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/in-transit 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.
• …
ZDO
EORTC-18081Adjuvant Pegylated-Interferon-alpha2b (Sylatron TM) for 2 Years Versus
Observation in Patients With an Ulcerated Primary Cutaneous Melanoma WithT(2-4)bN0M0: a Randomized Phase III Trial of the EORTC Melanoma Group
• Essen
• Kiel
• Lübeck
• Köln
• Heidelberg
• Mainz
• Mannheim
• Würzburg
ZDO
Stadium III
ZDO
EORTC-18071Adjuvant 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
The Lancet Oncology 2015 16, 522-530DOI: (10.1016/S1470-2045(15)70122-1)
ZDO
EORTC-18071Adjuvant 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
MK3475-054 / EORTC-1325Adjuvant 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
RANDOMIZATION
ARM APembrolizumab 200mg IV Q3
for 1 Year
ARM BPlacebo IV Q3 for 1 Year
Crossover possible after PD
1:1
Primary Objectives: Recurrence-free survival (also in the subgroup of patients with PD-L1-positive tumor expression)
ZDO
MK3475-054 / EORTC-1325Adjuvant 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
MK3475-054 / EORTC-1325Adjuvant 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
ZDO
MK3475-054 / EORTC-1325Adjuvant 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 14 211
Austria 2 20
Belgium 3 28
Czech Republic 1 15
Denmark 3 80
Finland 1 20
France 18 200
Germany 13 121
Russia 3 70
ZDO
MK3475-054 / EORTC-1325Adjuvant 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-2016 11:59 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
ZDO
Stadium IV
ZDO
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
Therapy
Follow-Up: every 3 months after last treatment (until end of study)
End of study: LPLV FU of LP for a maximum of 2 years
Randomization
Arm ANivolumab Monotherapy
Arm BNivolumab + Ipilimumab
Arm CDouble Placebo Control
End of treatment visit
Treatment week 1-12
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)
IMMUNEDA 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
Study Arm
w1 w2 w3 w4 w5 w6 w7 w8 w9 w10 w11 w12
A
Nivo3mg/kg+Ipi-Placebo
Nivo3mg/kg
Nivo-Placebo+Ipi-Placebo
Nivo3mg/kg
Nivo3mg/kg+Ipi-Placebo
Nivo3mg/kg
Nivo-Placebo+Ipi-Placebo
Nivo3mg/kg
B
Nivo1mg/kg+Ipi3mg/kg
Nivo-Placebo
Nivo1mg/kg+Ipi3mg/kg
Nivo-Placebo
Nivo1mg/kg+Ipi3mg/kg
Nivo-Placebo
Nivo1mg/kg+Ipi3mg/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.
IMMUNEDA 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
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).
IMMUNEDA 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 ZentrenMannheim
Hannover
BuxtehudeRegensburg
Heilbronn
BerlinMünster
GeraMünchen
DresdenLudwigshafenEssen
LübeckMainz
Erfurt
Tübingen
LeipzigHeidelbergKiel
MindenFrankfurt
IMMUNEDA 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
MO28848 / EADO-NEO-VCNeoadjuvant 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
Endpoints:• Primary Endpoint: Percent of patients who actually become resectable and are
resected• Secondary Endpoint: Progression-free survival, Overall survival(OS), Safety-
tolerability, 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
tissueExclusion 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
MO28848 / EADO-NEO-VCNeoadjuvant 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
HannoverBuxtehudeEssenMainzTübingenKiel
MO28848 / EADO-NEO-VCNeoadjuvant 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
PH-L19IL2TNF-02/15Randomisierte, offene, kontrollierte, multizentrische Phase III Studie zur Bestimmung der Wirksamkeit der neoadjuvanten intratumoralenBehandlung 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 21
4 P
atie
nte
n, 1
:1
Op innerhalb 4 Wochen
4 Injektionen, 1xWoche, Op 4 innerhalb 4 Wochen
Follo
w-U
p
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• BiomarkersInclusion 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 0-1Exclusion criteria: • Distant metastases• Uveal or mucosal melanoma
ZDO
Teilnehmende Zentren
HannoverEssenHeidelbergTübingenKiel
PH-L19IL2TNF-02/15Randomisierte, 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
PV10-MM-31PV-10 Intralesional Injection vs Systemic Chemotherapy or Oncolytic
Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma
• 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).
22
5 P
atie
nte
n, 2
:1
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.
Follo
w-U
p
PV-10 to all study lesions d1, q28 until CR, PD or study termination.
ZDO
Endpoints:• Primary Endpoint: Progression-free survival (PFS) • Secondary Endpoint: Complete response rate, Duration of complete response, OS• Safety and tolerabilityInclusion 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 beat 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) 0-2Exclusion criteria: • Presence or history of visceral melanoma metastasis• Presence of active nodal metastases
PV10-MM-31PV-10 Intralesional Injection vs Systemic Chemotherapy or Oncolytic
Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma
ZDO
Teilnehmende Zentren
KielHannoverEssenQuedlinburgTübingenDresdenMainzBerlin
PV10-MM-31PV-10 Intralesional Injection vs Systemic Chemotherapy or Oncolytic
Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma
Haut-
Tumor-
Zentrum
Hannover
HTZHAbteilung und/oder Titel
Abteilung und/oder Titel
Datum
Melanom palliativ –
Immunonkologisch
Ralf GutzmerKlinik für Dermatologie, Allergologie und Venerologie
Haut-
Tumor-
Zentrum
Hannover
HTZH
HTZH
Gliederung
T-VEC
• T-VEC Monotherapie
• T-VEC plus Ipilimumab
• T-VEC plus Pembrolizumab
Keynote 252 (MSD/Merck)
BoneMet (IIT, Hannover/Essen)
HTZH
Was ist T-VEC?
Talimogene Laherparepvec
Modifiziertes Herpesvirus
HTZH
Effekte von T-VEC
Lawler&Chiocca, J Clin Oncol 2015
HTZH
T-VEC: Monotherapie-Studie (Study T-Vec 20120325)
Multicenter, Open-label, Single-arm Trial to Evaluate theCorrelation 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
HTZH
T-VEC: Monotherapie-Studie (Study T-Vec 20120325)
HTZH
Estimated Enrollment: 110Global Study Start Date:Recruitment closed
April 2015Q2/2016
Estimated Study Completion Date: November 2018Estimated Primary Completion Date: December 2017 (Final data collection
date for primary outcome measure)
T-VEC: Monotherapie-Studie (Study T-Vec 20120325)
HTZH
Weltweit 45 Studienzentren4 deutsche Studienzentren:• Essen• Frankfurt/Main• Hannover• Heidelberg
2 österreichische Studienzentren:• Salzburg• Wien
14 Patienten in Deutschland rekrutiert
T-VEC: Monotherapie-Studie (Study T-Vec 20120325)
HTZH
Ipilimumab ± T-Vec in unresected melanoma (Study T-Vec 20110264)
HTZH
Global Study Start Date: February 2013Estimated Study Completion Date: November 2017Estimated Primary Completion Date: May 2016 (Final data collection date
for primary outcome measure)
Ipilimumab ± T-Vec in unresected melanoma (Study T-Vec 20110264)
Erste Ergebnisse am 28.09.2016 auf dem ESMO Kongress erwartet
HTZH
Weltweit 40 Studienzentren
3 deutsche Studienzentren:• Göttingen• Kiel• Tübingen
10 Patienten in Deutschland rekrutiert
Ipilimumab ± T-Vec in unresected melanoma (Study T-Vec 20110264)
HTZH
Pembrolizumab +- T-VEC (Study T-Vec 20110265)
• 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)
HTZH
(abgeschlossen, nicht in D)
Pembrolizumab +- T-VEC (Study T-Vec 20110265)
HTZH
MASTERKEY-265 Phase 3 Study Design
N = 660
1:1
N = 330
N = 330
Pembrolizumab 200mg IV Q3W
T-VEC Intralesional
Pembrolizumab 200mg IV Q3W
T-VEC placebo Intralesional
Primary Endpoints: PFS and OS
R
• Unresectable stage III or
IV melanoma
• Treatment naive
– Prior BRAFi allowed
• Injectable lesions
Long G V et SMR 2015
HTZH
62 Zentren weltweit
Studienzentren D
• Dresden
• Hannover
• Kiel
• Regensburg
• Tübingen
• Weitere in Planung
Masterkey 265
Studienzentren CH
• Geneve
• Lausanne
• Zürich
Studienzentren A
• Salzburg
HTZH
T-VEC
Ansprechpartner bei Amgen:
Dr. med. Markus Schill
Senior Medical Advisor Immuno-Oncology
AMGEN GmbH
Hanauer Str. 1, 80992 München
Tel.: +49 (0)89 – 149 096 1492
Fax: +49 (0)89 – 149 096 2492
HTZH
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)
HTZH
Keynote 252-Studie
Epacadostat: IDO1-Inhibitor
IDO1: Indoleamine 2,3 dioxygenase 1, metabolisiert Tryptophan
[Not approved] FOR MEDICAL INFORMATION PURPOSES ONLY. NOT FOR PROMOTIONAL USE. DO NOT COPY, DISTRIBUTE OR OTHERWISE REPRODUCE.
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 3 1 2 0 0
PR 7 0 3 4 0
SD 4 1 2 0 1
DCR (CR+PR+SD) 14 (74) 2 (100) 7 (58) 4 (100) 1 (100)
PD 5 (26) 0 5 (42) 0 0
52
*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.
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 3 1 2 0 0
PR 7 0 3 4 0
SD 4 1 2 0 1
DCR (CR+PR+SD) 14 (74) 2 (100) 7 (58) 4 (100) 1 (100)
PD 5 (26) 0 5 (42) 0 0
53
*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
HTZH
Keynote 252 – Endpunkte
Primär
• Progression-free survival (RECIST 1.1)
• Overall survival
Sekundär
• Objective response rate (RECIST 1.1)
• Safety and tolerability
HTZH
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
HTZH
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
HTZH
Keynote 252 – Logistik
• 600 Patienten
• 112 Zentren weltweit
• Zentren D
– Buxtehude
– Essen
– Hannover
– Kiel
– Tübingen
• Zentren CH
– Geneve
– Lausanne
– Zürich
HTZH
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
HTZH
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
HTZH
BoneMet - Endpunkte
• Primär
– Anzahl aktivierter T-Zellen im peripheren Blut
– Induktion von Interferon gamma im Plasma
• Sekundär
– Sicherheit
– Verträglichkeit
– Effektivität
HTZH
BoneMet - Logistik
• 20 Patienten
• 4 Zentren
• Sponsor: Hannover Clinical Trial Center
• LKP: Ralf Gutzmer, Hannover
• Translationale Untersuchungen: Jürgen Becker, Essen
• Beginn Rekrutierung: Q1/2017
Onkologisches Zentrum
Studientreffen ADO Dresden, 22.9.2016
Immunonkologische Studien, Melanom
PD Dr. med. Patrick Terheyden, MA
Stv. Klinikdirektor, Klinik für Dermatologie
Leiter des Hautkrebszentrums
05.1
0.2
016
POPULATION TREATMENT
Part 1 – Double-blind ** Part 2 – Open-label
ENDPOINTS
Phase IIIb/IV Checkmate 511A Randomized, Double-blinded Phase IIIb/IV Study of Nivolumab 3 mg/kg plus Ipilimumab 1 mg/kg vsNivolumab 1 mg/kg plus Ipilimumab 3 mg/kg in Treatment-naïve Subjects With Advanced Melanoma
Eligible patients
with unresect-
able stage III or
IV melanoma
(n=346)
• Treatment-naïve
• ECOG 0-1
Stratified by:
• PD-L1
expression*
• AJCC M stage
Nivolumab
3 mg/kg +
Ipilimumab
1 mg/kg Q3W
for 4 doses
Nivolumab
1 mg/kg +
Ipilimumab
3 mg/kg Q3W
for 4 doses
Treat until
progression***
OR unacceptable
toxicity****
Primary endpoint:
• Incidence of
drug-related
grade 3-5 AEs#
Secondary EPs:
• ORR#
• OS# & PFS#
Nivolumab
Flat Dose
480 mg Q4W(30 min infusion)
6 W
EE
KS
**6 W
EE
KS
**
R
1:1
* 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.
www.clinicaltrials.gov (NCT02714218) – Status September 2016
AEs = Adverse Events, EP = Endpoint, ORR = Objective Response Rate, OS = Overall Survival, PFS =
Progression Free Survival
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 Criteria1:
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 Criteria1:
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 2022
Phase IIIb/IV Checkmate 511A Randomized, Double-blinded Phase IIIb/IV Study of Nivolumab 3 mg/kg plus Ipilimumab 1 mg/kg vsNivolumab 1 mg/kg plus Ipilimumab 3 mg/kg in Treatment-naïve Subjects With Advanced Melanoma
www.clinicaltrials.gov (NCT02714218) – Status September 20161 For more information please visit www.BMSStudyConnect.com
POPULATION ENDPOINTSTREATMENT
www.clinicaltrials.gov (NCT02599402) – 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
* 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.
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 treatment-
related, select AEs
Secondary EPs:
• Incidence, mTTO &
mTTR of all grade
3-4 select AEs#
• ORR, PFS & OS
Phase IIIb/IV Checkmate 401A 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
68
Phase IIIb/IV CA209-401A 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 Criteria1:
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.
www.clinicaltrials.gov (NCT02599402) – Status September 20161 For more information please visit www.BMSStudyConnect.com
69
Phase IIIb/IV CA209-401A 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 Criteria1:
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, neo-
adjuvant, 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 2021
www.clinicaltrials.gov (NCT02599402) – Status September 20161 For more information please visit www.BMSStudyConnect.com
70
Phase I/II CA186-107A 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
www.clinicaltrials.gov (NCT02253992) – Status September 2016
71
Phase I/II CA186-107A 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 Criteria1:
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 Criteria1:
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
www.clinicaltrials.gov (NCT02253992) – Status September 20161 For more information please visit www.BMSStudyConnect.com
Phase I/II CA186-107A 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 2019
www.clinicaltrials.gov (NCT02253992) – Status September 2016
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
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
Metastatic melanoma (>= second-line):
A randomized phase II trial
Combined modularized therapy versus DTIC (Mel001)
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
Treatment until progression or intolerable toxicity
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
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.
Planned Study Timelines:
Recruitment of patients is scheduled to
December 2017
The minimum follow-up time from last patient
recruited is 12 months
Teilnehmende Zentren
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
22 Patienten ausstehend
Investigator-initiated trialSponsor: Universitätsklinikum Regensburg
Finanzielle Unterstützung durch Pfizer
Ansprechpartner:
Prof. Dr. Albrecht Reichle:
Tel.: +49-941-9445540
PD Dr. Sebastian Haferkamp
Tel.: +49-941-9449605
Studienzentrale: Frau Montag
Tel.: +49-941-9445536
Onkologisches Zentrum
Studientreffen ADO Dresden, 22.9.2016
Immunonkologische Studien, Melanom
Diskussion
05.1
0.2
016
NRAS+; BRAF Wildtyp
Katharina C. Kähler
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
•Augsburg
•Berlin
•Bonn
•Buxtehude
•Düsseldorf
•Erlangen
•Essen
•Frankfurt am Main
•Hamburg
•Hannover
•Kiel
•Köln
•Leipzig
•Magdeburg
•Mainz
•München
•Münster
•Plauen
•Tübingen
•Würzburg
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= 0.0022), 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
Ansprechpartner:Array
Zentren in Deutschland
• Essen
• Buxtehude
• Gera
• Heidelberg
• Homburg
• Ludwigshafen
• Lübeck
• München
• Hornheide
NIPAWILMA
Studienstart: Jan 2015 (1. Zentrum geöffnet)
FPI: 17.03.2015
Phase I abgeschlossen
ermitteltes Dosislevel Nintedanib: 200mg BID
Doppel-blinde Phase II ab KW34 gestartet
Rekrutierungs-Übersicht Phase I:
Site
No.
Offene
Zentren
Offen
seit
Pat.
gescree
nt
Erster
Pat.
gescreent
Letzter
Pat.
gescreent
Patienten
randomisie
rt
Erster Pat.
randomisie
rt
Letzter Pat.
randomisie
rt
01 Essen07.01.201
510
21.01.201
5
26.02.201
66 17.03.2015 07.03.2016
02 München08.01.201
53
12.01.201
5
06.10.201
50 - -
03 Heidelberg24.02.201
56
19.03.201
5
15.04.201
61 26.04.2016 -
04 Buxtehude10.03.201
51
26.08.201
5- 0 - -
05Münster/Hornheid
e
16.04.201
51
03.09.201
5- 1 15.10.2015 -
06 Gera21.10.201
50 - - 0 - -
07 Homburg06.01.201
50 - - 0 - -
08 Ludwigshafen20.11.201
52
29.01.201
6
04.02.201
62 25.02.2016 25.02.2016
09 Lübeck15.01.201
61
28.01.201
6- 0 - -
10 UK Münster03.02.201
60 - - 0 - -
Sum: 24 10
PACMEL
Studienstart: Okt 2014 (1. Zentrum geöffnet)
FPI: 03.12.2014
Rekrutierungsende: 31.03.2016
Last Patient Last Visit: voraussichtlich 12/2016
Site No.
offene Zentren
Offen seit
Pat.
gescreent
letzter
Pat.gescreent
letzter
Pat.
gescreent
Pat.
randomisiert
erster Pat.
randomisiert
letzter Pat.
randomisie
rt
01 Essen17.10.201
417
10.11.201
4
18.03.201
613 05.12.2014 07.04.2016
02 Tübingen12.11.201
44
28.07.201
5
12.01.201
63 25.08.2015 15.01.2016
03 Köln19.11.201
45
16.12.201
4
29.07.201
53 02.02.2015 10.08.2015
04 Erfurt08.01.201
54
16.03.201
5
18.09.201
51 14.04.2015 -
05 Kiel03.02.201
50 - - 0 - -
06 Minden18.02.201
53
15.07.201
5
28.01.201
62 20.07.2015 09.02.2016
07Regensbur
g
19.03.201
50 - - 0 - -
08 Berlin23.03.201
107.04.201
- 1 11.05.2015 -
Targeted BRAF-Phase I/II-
Studien
Lisa Zimmer
Folie 112TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
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 113TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
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 114TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
BOTTOM
• 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
Kohorte A Kohorte B Kohorte C
Folie 115TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
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
BOTTOM
Folie 116TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
Timelines:
BOTTOM
Rekrutierungsdauer: 15 Monate
Einschluss erster Patient: Q4 2015
Einschluss letzter Patient: Q2 2017
Studienende: Q2 2018 (= 1 Jahr nach 1. Therapiegabe
des letzten Patienten)
Folie 117TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
Aktuelle Zahlen:
BOTTOM- Rekrutierung
• LKP: Dirk Schadendorf
• Studienstart: Jul 2015 (1. Zentrum geöffnet)
• FPI: 30.11.2015
• Stand 8.9.2016, 7 Zentren in Deutschland geöffnet
Folie 118TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
Ansprechpartner UK Essen:
Julia Grimm
Mail: [email protected]
Phone: +49201-7232325
Ansprechpartner Alcedis:
Dr. Joachim Stump
Winchesterstr. 3
D- 35394 Gießen
Mail: [email protected]
Phone: +49 (0) 641/ 94436-0
BOTTOM
Folie 119TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
BOTTOM - Studientreffen
Folie 120TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
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 121TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
• 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
LOGIC II CLGX818X2109
Folie 122TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
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
LOGIC II CLGX818X2109
Folie 123TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
Timelines:
• Einschluss erster Patient: Juli 2014
• Einschluss letzter Patient: 9. November 2015
• Voraussichtliches Studienende: 6. Januar 2017
LOGIC II CLGX818X2109
Folie 124TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
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
LOGIC II CLGX818X2109
Folie 125TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
Aktuelle Zahlen:
LOGIC II CLGX818X2109
Folie 126TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
Ansprechpartner:
ARRAY und PPD
LOGIC II CLGX818X2109
Folie 127TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
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
ImmunoCobiVem
Folie 128TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
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
Reminder System)
Folie 129TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
ImmunoCobiVem – eMARS-Konzept
Run-In Phase (3 Monate = 12 Wochen)
Papier-Med.-Diary (Hauptstudie) Alcedis eMARS
• Patient: führt Papier-Med.-Diary und bringt dieses zu Visiten mit
• Arzt: überprüft Med.-Diary bei Visite und pflegt dies ins eCRF ein
• Patient: führt online Med.-Diary
• eMARS: erinnert Patient bei Nichteinnahme per SMS
• Arzt: überprüft Med.-Diary im eCRF bei Visite
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
Pharmakovigilanz:
Prüfen der Patienten-
Einträge nach
festgelegtem Schema
Randomisation Phase
Ende der Run-In Phase:• Patient: beantwortet Patienten-Fragebogen elektronisch
Patienten können optional eMARS während Einnahme von Cobimetinib und Vemurafenib in Randomisation Phase weiter nutzen
Auswertung der Medikationsadhärenz nach 18 Monaten Studienlaufzeit
Technischer Support:
Telefon-Hotline und FAQ
im eCRF
Per Tablet am Zentrum
Folie 132TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
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
ImmunoCobiVem
Folie 133TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
Timelines:
ImmunoCobiVem
Rekrutierungsdauer: 15 Monate
Initiierung der ersten Zentren: ab 26.9.2016
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 134TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
• LKP: Dirk Schadendorf
• Europaweite Rekrutierung, insgesamt 30 Zentren, davon 20 in Deutschland
ImmunoCobiVem
Folie 135TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
ImmunoCobiVem- 10 Zentren im Ausland
Folie 136TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
ImmunoCobiVem
Ansprechpartner UK Essen:
Julia Grimm:
Mail: [email protected]
Phone: +49201-7232325
Ansprechpartner Alcedis:
Dr. Joachim Stump
Winchesterstr. 3
D- 35394 Gießen
Mail: [email protected]
Phone: +49 (0) 641/ 94436-0
Folie 137TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
ImmunoCobiVem - Studientreffen
Folie 138TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
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 139TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
• 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
• Primäres Studienziel: Sicherheit und Verträglichkeit
IMMU-TARGET – Studienaufbau Phase 1
Folie 140TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
• Primärer Endpunkt: PFS, PFS-Rate nach 12,18, 24 Monaten
• Sekundärer Studienendpunkte: Sicherheit, ORR, Overall survival, OS-
Rate nach 1- und 2-Jahren
IMMU-TARGET – Studienaufbau Phase 2
Folie 141TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
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
IMMU-TARGET
Folie 142TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
Timelines:
Studienstart (First Patient First Visit): Q4 2016
Rekrutierungszeitraum 24 Monate
Rekrutierungsende (Last Patient First Visit): Q4 2018
Studienende (Last Patient Last Visit): Q4 2020
Datenbankschluss Q4 2021
IMMU-TARGET
Folie 143TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
IMMU-TARGET
• LKP: Dirk Schadendorf
• 17 Zentren in Deutschland
Folie 144TitelTargeted BRAF-Phase II+III22.9.2016 | L.Zimmer
IMMU-TARGET
Ansprechpartner UK Essen:
Julia Grimm:
Mail: [email protected]
Phone: +49201-7232325
Ansprechpartner Alcedis:
Dr. Joachim Stump
Winchesterstr. 3
D- 35394 Gießen
Mail: [email protected]
Phone: +49 (0) 641/ 94436-0
Hautklinik und PoliklinikRhein-Main
HautkrebsZENTRUM
CL
Impfstudien/Uveamelanom
Carmen Loquai
23.09.2016
Hautklinik und PoliklinikRhein-Main
HautkrebsZENTRUM
CL
Gliederung
Impfstudie
RP-0003-01/Lipo-MERIT Studie
Uveamelanomstudie
FOCUS-PHP-OCM-301 Studie
Hautklinik und PoliklinikRhein-Main
HautkrebsZENTRUM
CL
RB_0003-01: Lipo-MERIT
Clinical first-in-human study dose escalation study evaluatingthe safety and tolerability of intravenous administration of atetravalent RNA-lipoplex cancer vaccine targeting the tumor-associated antigens NY-ESO-1, tyrosinase, MAGE-A3, and TPTEin patients with advanced melanoma
Hautklinik und PoliklinikRhein-Main
HautkrebsZENTRUM
150TRON gGmbH
Ultrasound-
guided
intranodal
injection
Local DC targeting
Tumor
Lymph nodeThymus
Spleen
Peyer‘s patch
Bone marrow
Excellent preclinical safety profile
Strong therapeutic antitumor activity
mRNA and DCs meet directly at injection site
Systemic DC targeting
Intravenous
injection
mRNA Vakzine für optimiertes DC-Targeting in vivo
MERIT (NCT01684241)
IVAC MUTANOME (NCT02035956)
Liposomal RNA vaccine targeting to DC
Universally applicable for almost all types of tumor antigen
Induction of combined innate and adaptive immunity
Triggering of type I IFN network
Strong therapeutic antitumor activity
RNA
RNA(LIP)
Kranz, Diken et al, Nature 534, (June 2016)
Hautklinik und PoliklinikRhein-Main
HautkrebsZENTRUM
CL
RB_0003-01: 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: 39-51 (5-6 Kohorten)
Hautklinik und PoliklinikRhein-Main
HautkrebsZENTRUM
CL
RB_0003-01: Lipo-MERIT
Erster Patienteneinschluß: 27.05.2015
Letzter Patienteneinschluß: voraussichtlich Q4 2017
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
Hautklinik und PoliklinikRhein-Main
HautkrebsZENTRUM
CL
Gliederung
Impfstudie
RP-0003-01/Lipo-MERIT Studie
Uveamelanomstudie
FOCUS-PHP-OCM-301 Studie
Hautklinik und PoliklinikRhein-Main
HautkrebsZENTRUM
CL
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
Hautklinik und PoliklinikRhein-Main
HautkrebsZENTRUM
CL
Studiendesign
Uveamelanom,
überwiegend
hepatisch
metastasiert
Melphalan/HDS* 3,0
mg/kgKG, bis zu 6x
Kontrolle: DTIC,
transarterielle
Chemoembolisation
(TACE), Ipilimumab,
Pembrolizumab
*Hepatic Delivery System
Randomisierung: 1:1
Hautklinik und PoliklinikRhein-Main
HautkrebsZENTRUM
CL
Hepatic Delivery System (Delcath Device System)
Hautklinik und PoliklinikRhein-Main
HautkrebsZENTRUM
CL
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
Melanom-Hirnmetastasen
Friedegund Meier, Dresden
ADO - Studientreffen
Dresden, 22.09.2016
A Phase II, Open-Label, Multicentre
Study of Dabrafenib plus Trametinib
in Subjects with BRAF Mutation-
Positive Melanoma that has
Metastasized to the Brain
BRF117277 / COMBI-MB
Sponsor: Novartis
Clinicaltrials.gov: NCT02039947
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
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
Cohort D* (N=15)
V600D/E/K/R (locally confirmed)
Symptomatic, ECOG 0-2
With or without prior local therapy
• Cutaneous melanoma
• ≤ 2 systemic therapies
• ≥1 measurable brain lesion
N = 120
Dabrafenib 150 mg BID +
Trametinib 2 mg QD
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: NCT02039947
*Rekrutierung beendet für
Kohorten B-D
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: NCT02039947
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
* delayed participation of Germany due to BfS approval
Clinicaltrials.gov: NCT02039947; data on file.
Timelines:
• FPFV (global): 21. Feb 2014
• FPFV (Germany)*: 04. Dec 2014
• LPFV : 22 July 2016
• 1st results to be presented @
ASCO 2017 (planned)
Ansprechpartner des Sponsors
Kerstin Patzolt (project management)
Phone +49 6105-9430-246
Clinicaltrials.gov: NCT02039947
Buparlisib in Melanoma Patients
Suffering From Brain Metastases
CBKM120ZDE01T / BUMPER
Sponsor: Universitätsklinikum Tübingen
Clinicaltrials.gov: NCT02452294
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
•BRAFwt failed prior
immune checkpoint inhibitor
•BRAFV600 failed BRAFi
•Not eligible for
surgery or radiosurgery
•Melanoma brain metastases
•Asymptomatic, symptomatic
•ECOG 0-2
N = 22
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: NCT02452294
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 Melanomhirnmetastasen-
zellen 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
MEKi
PI3Ki
Melanom-Hirnmetastasen:
PI3K / AKT – Inhibitoren - Rationale
16 20 23 27 30
16 20 23 27 30
days p.o.
days p.o.
M13 B
up
arl
isib
M14 S
HA
MDer PI3K-Inhibitor Buparlisib hemmt
das Wachstum von Melanom-HirnmetastasenMRI
Niessner et al, Clin Cancer Res 2016
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: NCT02452294
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: NCT02452294
Rekrutierung
Aktueller Status (13. Sept. 2016)
• 9 patients enrolled
• 2 active sites in Germany
Thomas Eigentler, Tübingen
Claus Garbe, Tübingen
Friedegund Meier, Dresden
Clinicaltrials.gov: NCT02452294
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)
Ansprechpartner
PD Dr. Thomas Eigentler
Phone +49 7071 298 5748
Prof. Dr. Friedegund Meier
Phone +49 351 458 19505
Clinicaltrials.gov: NCT02452294
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
CA209-429 / BRAINIP trial
Sponsor: Universitätsklinikum Tübingen
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
•Without and with previous therapy
•Not eligible for surgery or
radiosurgery
• > 4 symptomatic melanoma
brain metastases
•ECOG 0-2
•Life expectancy >3 months
N = 68
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
BRAINIP
Ein- und Ausschlusskriterien
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
BRAINIP
Main exclusion criteria
• 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).
Ein- und Ausschlusskriterien BRAINIP
Rekrutierung
Aktueller Status (13. Sept. 2016)
• 0 patients enrolled
• 15 sites in Germany (planned)
Clinicaltrials.gov: NCT02452294
Timelines:
• Study Start Date (FPFV)
Date: October 2016 (planned)
• LPLV
Date: September 2018
• End of Study
Date: September 2019
BRAINIP
Ansprechpartner
PD. Dr. Thomas Eigentler
Phone +49 7071 298 5748
Prof. Dr. Claus Garbe
Phone +49 7071 298 7110
Clinicaltrials.gov: NCT02452294
BRAINIP
Radiomics to identify MRI parameters
that might be predictive of good response or side effects179
Radioonkoloogie
E. Troost
Dermatoonkologie
F. Meier
Neuroradiologie
J. Linn
Dresden
Tübingen
Heidelberg
ML30010 RadioCoBrim
FPI Q1 2017 (planned)
1. Shi H et al. Cancer Discov. 2014;4:69-79. 2. Trunzer K et al. J Clin Oncol. 2013;31:1767-1774. 3. Paraiso K et al. Br J Cancer. 2010;102:1724-1730. 4. Long GV et al. J Clin Oncol. 2014;32(5S):9011. 5. Ribas A et al. Lancet Oncol. 2014;15:954-965. 6. Su F et al. New Engl J Med 2012;366:207-215.
Rationale
Most common mechanism of acquired resistance to
vemurafenib is MAPK reactivation through MEK1,2
MEK + BRAF inhibition prevents the development of acquired resistance in preclinical models3
MEK + BRAF inhibition (dabrafenib + trametinib4 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 inhibition6
ERK
Uncontrolled proliferation
COT
Increased PDGFRβ/IGF1R activity
RAS mutation
MEK mutation
COT up-regulation
Spliced BRAF isoforms
BRAFiT
MEKiT
CRAF
MEK
BRAFV600
Adapted with permission from AACR.1
RAS
PFS, progression free survival.
Melanom-Hirnmetastasen:
BRAFi + MEKi - Rationale
Therapiestudien bei kutanen
Lymphomen
Jan. P. Nicolay
Studientreffen ADO 2016
Name I Folie 1 I Datum
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
Brentuximab Vedotin (C25001)
Millennium Pharmaceuticals, Inc. /
Seattle Genetics, Inc.
Name I Folie 1 I Datum
Studienaufbau C25001
Phase III RCT
Brentuximab-Vedotin i.v. alle 21 Tage
versus
Bexaroten 150 - 300 mg/m² tgl. oder
Methotrexat 5 - 50 mg p.o. wö. (physicians choice)
bei PD im Kontrollarm crossover (SGN-035-10)
Name I Folie 1 I Datum
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
Brentuximab Vedotin (C25001)
Zentren
Berlin
Kiel
Krefeld
Mannheim
Mainz
Minden
Würzburg
LKP:
M. Weichenthal, Kiel
Rekrutierungsstand:
Deutschland: 6
weltweit: 132
1.9.2015 Studie komplett
Name I Folie 1 I Datum
Pressemitteilung 1.8.2016
Alcanza C25001
ORR4 56.3 % im ADCETRIS-Arm
versus 12.5 % im Bexa/MTX-Arm
p <0.0001
Alle sekundären Endpunkte inclusive Lebensqualität significant besser
Präsentation ASH 12/2016 San Diego
Name I Folie 1 I Datum
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(0761-010)
NCT01728805
Sponsor: Kyowa Hakko Kirin
Pharma, Inc.
Name I Folie 1 I Datum
Studienaufbau – KW 0761-010
317 Patienten
Vorinostat 400 mg/d
oral
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
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
Timelines
Studienstart: 11/2012
Rekrutierungsende: 11/2015
Studienende: 2019
Geplante Datenveröffentlichung: 2019
Name I Folie 1 I Datum
Aktuelle Zahlen
Teilnehmende Zentren:
•Weltweit 73 Zentren
•2 Zentren in Deutschland:
• Mannheim
• Münster
Rekrutierung komplett (373 Patienten)
Name I Folie 1 I Datum
Ansprechpartner des Sponsors
Name: Marietta Keckeis
E-Mail: [email protected]
Telefonnummer: +49(0) 172 8571 637
Name I Folie 1 I Datum
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: 2014-000924-11)
NCT02546440
IST-Sponsor: Medizinische
Fakultät Mannheim/Heidelberg
Name I Folie 1 I Datum
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
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
Timelines
Studienstart: 02/2016
Studienende: Ende 2018
Geplante Datenveröffentlichung: September
2019/ADO-Tagung
Name I Folie 1 I Datum
Aktuelle Zahlen
Teilnehmende Zentren (Rekrutierungszahl):
•Mannheim (4/25)
•Kiel
•Krefeld (1/25)
•Ludwigshafen
•Minden (1/25)
•Würzburg
Name I Folie 1 I Datum
Ansprechpartner des Sponsors
LKP und Sponsorvertreter: Jan Nicolay
E-Mail: [email protected]
Telefonnummer: 0621-3832280
Name I Folie 1 I Datum
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
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
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
Timelines
Studienstart: 10/2016
Rekrutierungsende: 12/2019
Studienende: noch nicht absehbar
Geplante Datenveröffentlichung: noch nicht
absehbar
Name I Folie 1 I Datum
Aktuelle Zahlen
Teilnehmende Zentren:
•Weltweit 50 Zentren in 10 Ländern geplant
•?? Zentren in Deutschland
Rekrutierung noch nicht gestartet
Name I Folie 1 I Datum
Ansprechpartner des Sponsors
Sponsor: 4SC, Martinsried; Dr. Daniel Vitt
Telefonnummer: +49 (0)89 7007630
LKP: Prof. Rudolf Stadler
Telefonnummer: +49 (0)571 7904501
Organisation: ICON; Melanie Milde
Telefonnummer: +49 (0)6185 4371251
Email: [email protected]
Merkellzellkarzinom
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
CA184-205 - ADMEC
Universitätsklinik Essen
BMS
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
ADMEC –
Wichtigste Ein- und Ausschlusskriterien
• MCC Stage I – III,
• no evidence of disease
• ECOG: 0 and 1
• Adequate hematologic, liver and renal
function
ADMEC – Teilnehmende ZentrenADMEC
Organisation Abteilung Nachname Vorname
Universitätsklinikum EssenKlinik 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-HolsteinKlinik für Dermatologie, Venerologie und Allergologie
Kähler Katharina C.
Universitätsklinik Carl Gustav Carus der Technischen Universität Dresden
Dermatologie Meyer Friedegund
Nationales Centrum für Tumorerkrankungen Universitätsklinikum Heidelberg
Dermatologie Hassel Jessica Cecile
Medizinische Hochschule Hannover Dermatologie Gutzmer Ralf
Charité Dermatologie Kiecker Felix
Gera Dermatologie Kaatz Martin
Münster Hornheide Onkologie Fluck Michael
ADMEC - Aktueller Stand
• Studienstart: September 2014
• Studienende: September 2017
Anzahl Patienten gescreent: 34
Anzahl Patienten randomisiert: 23
Siteno. City Country Opensince Numberofpatientsscreened Firstpatientscreened Lastpatientscreened Numberofpatientsrandomized Firstpatientrandomized Lastpatientrandomized
01 Essen Germany 24.06.14 8 04.09.14 09.09.16 4 28.01.16 23.05.16
02 Buxtehude Germany 09.07.14 1 12.08.15 12.08.15 1 24.08.15 24.08.15
03 Tübingen Germany 02.10.14 5 31.03.15 25.04.16 5 01.07.15 24.05.16
04 Kiel Germany 12.08.14 3 23.02.16 09.08.16 1 10.03.16 10.03.16
05 München Germany 13.10.14 0 0
06 Dresden Germany 09.10.14 4 28.10.14 08.12.15 3 04.11.14 04.11.15
07 Heidelberg Germany 28.07.14 9 14.08.14 04.08.16 5 16.09.14 31.08.16
08 Berlin Germany 07.03.16 0 0
09 Gera Germany 17.02.16 0 0
10 Hannover Germany 11.02.16 3 07.03.16 14.04.16 3 18.04.16 02.06.16
11 Münster Germany 17.12.15 1 08.01.16 08.01.16 1 22.01.16 22.01.16
Summe 34 23
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
A Phase II study of the tumour-targeting
human F16IL2 monoclonal antibody-
cytokine fusion protein in combination with
paclitaxel versus
paclitaxel alone in patients with Merkel cell
carcinoma
IMMOMEC
Philogen
European Commission
IMMOMEC - Aktueller Stand
• Studienstart: Oktober 2013
• Rekrutierungsende: Juni 2016
• Studienende: Dezember 2016
Anzahl Patienten gescreent: 41
Anzahl Patienten randomisiert: 21
• Data Lock: Dezember 2016
JAVELIN MCC 200
A Phase II, open-label, multicenter trial to
investigate the clinical activity and safety
of MSB0010718C (avelumab) in subjects
with Merkel cell carcinoma
EMD Serono
TCR
T Cell
Tumor
Cell
MHC
Activated
Activation
PD-1
PD-L1
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:
NCT02155647
Javelin MCC 200 - Rekrutierung
Von: Foley, Grace [email protected]
Betreff: Follow-up - with Pfizer/Merck - Expert in MCC session meeting in Frankfurt Tuesday 20th September and Advisory
Board in Berlin Wednesday 23rd November
Datum: 7. September 2016 um 09:21
An: Becker Jürgen C. ([email protected]) [email protected]
Dear Jürgen,
I hope you enjoyed the rest of your weekend. It was great to meet you in person in Vienna and to chatfurther about the ‘Expert in MCC’ session and also the MCC Advisory Board in November in Berlin.
The Meet the expert session in Frankfurt – Tuesday 20th September- It will take place at the Leonardo Royal Hotel Mailänder Straße 1, 60598 Frankfurt - MAP
- I can confirm that your session will start at 17:30 -19:00 on Tuesday 20th September followed by
dinner.
- We have also reserved a room for the night of 20th September in the hotel.
In relation to the content of the presentation, as mentioned if you can share your slides on Friday 16th or
Monday 19th we would appreciate this.
We unfortunately do not have any specific cases on file that could be used other than the case presented atthe symposium.We are looking to collate them in the future but do not have a bank of cases available at the moment.
You mentioned that you may be able to obtain some cases from your colleagues. I list some information
below that I have to date, which includes a list of investigators/sites that have at least enrolled twopatients 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 STATESD'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
Reponses to Avelumab
Javelin MCC 200 – 1st Line Extension
TCR
T Cell
Tumor
Cell
MHC
Activated
Activation
PD-1
PD-L1
• 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:
NCT02155647
• Currently open European sites:
Anti PD-1 for advanced MCC
TCR
T Cell
Tumor
Cell
MHC
Activated
ActivationPD-1
PD-L1
• 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:
NCT02267603
Responses are Independent of
Viral or PD-L1 Status
BMS CA 209-358 (Nivo)
Non-Comparative, Two-Cohort, Single Arm,
Open-Label, Phase 1/2 Study of Nivolumab
(BMS-936558) in Subjects with
Virus-positive Solid Tumors
ClinicalTrials.gov - NCT02488759
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
BMS CA 209-358 (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
BMS CA 209-358 (Nivo)
SYNOPSIS REVIEW PACKAGE
(THIS DOCUMENT IS INTENDED FOR INTERNAL USE ONLY AND IS NOT TO BE DISTRIBUTED EXTERNALLY)
Page 4 of 19
This document is considered Bristol-Myers Squibb Company confidential information.
The information herein may not be disclosed or distributedwithout Bristol-Myers Squibb Company’s Prior approval.
Version Date: 06-Feb-2012
Document Owner: Shawn Pelletier
3.1.1.1 Viral status determination prior to entry
For the neoadjuvant arm, patients enrolled in the Gastric and SCCHN cohorts will be tested for
EBV and HPV, respectively, prior to administration of study drug. For each gastric and SCCHN
cohort, 16 patients with virus positive disease and 5 with virus negative disease will be enrolled.
No prior screening for HPV Gyn or MCC cohorts is necessary due to the high prevalence of viral
positivity and the technical aspects of the MCPyV assay. Viral positivity will be collected
retrospectively in the MCC and GYN cohorts.
Table 7.1.1.1-1: Testing for viral status prior to treatment
Arm Tumor Type Viral status required prior to study drug (Testing)
Neoadjuvant EBV Gastric YES (EBER)
HPV SCCHN YES (HPV 16 in situ hybridization,
Proposed Trial Design
Tumor Types•EBV Gastric•HPV SCCHN •HPV GYN (cervical/vulvar)•M CC
Screening Treatment
Bio
psy
/Ne
oA
dju
van
t
Follow-Up
Me
tast
atic
Up to 4 weeks
ORR
Tumor Types•EBV NPC•EBV Gastric•HPV SCCHN•M CC•HPV GYN (cervical/vulvar)
Treatment Options•Standard of Care † or •Nivolumab ‡ 3 mg/kg IV q14 days untiltoxicity or progression if medically eligible (i.e. meet criteria for metastatic cohort)
Nivo M onotherapy3mg/kg Q2wk
Until toxicity or progression
M in 12 weeks
SurvivalM ax 3 years
M in 12 weeks
• ≥ 1 priortreatment for m etastaticdisease
• ≥ 1 targetlesion
• ECOG PS: 0-1
•Imaging every 6 weeks startingat week 6 for the first year of
treatment. •Imaging every 12 weeks starting
at year 2 and beyond
Biopsy(Prior to 1st dose)
Nivo M onotherapy
3mg/kg x 2 doses
10 subjects ≥ S afety analysis ≥Addtional 6 subjects if ≥ 2 /10 have surgery delayed > 6 weeks due to AE
Biopsy or Surgical
Resection(Day 28)
N=16 with Virus + for each tumor typeN=5 with Virus – for each tumor type except MCC
Subsequent Treatment
N=23 for each tumor type
On-Treatment Assessment
online
Merkelzellkarzinomregister
der ADO
MCC-Register
finanzielle Unterstützung: keine
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
ZDOZentrum für Dermatoonkologie
Universitäts-Hautklinik TübingenPD Dr. med. Ulrike Leiter
18.06.16
Ulrike LeiterCentre of Dermato-Oncology
University of Tuebingen, Germany
Neue Studie beim epithelialen Tumoren
Plattenepithelkarzinom
A Phase II Study of REGN 28010, a Fully Human MonoclonalAntibody to PD-1 in Patients with Advances Cutaneous Squamouscell carcinoma
2 Gruppen
Group 1 Patients with metastatic CSCC: to distant sites or lymph nodes
Drug: REGN2810
Group 2 Patients with unresectable locally advanced CSCC
Drug: REGN2810
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
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
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
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
Plattenepithelkarzinom
Ansprechpartner : Prof. Hauschild, Kiel
Estimated Enrollment: 129Study Start Date: March 2016 jetzt Herbst 2016Estimated Study Completion Date: May 2019Estimated Primary Completion Date: May 2019
Plattenepithelkarzinom
Studienstart• Herbst 2016
Teilnehmende Zentren: • Essen• Kiel • Frankfurt• Berlin Charité• Dresden• Hannover• Tübingen
https://clinicaltrials.gov/show/NCT02760498
Weitere Studien mit dieser Substanz der Firma Regeneron sind fürdas
• Merkelzellkarzinom• Basalzellkarzinom
im nächsten Jahr geplant.
Europ. PI: Prof. Hauschild, Kielbei Fragen gerne kontaktieren
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 30.3.16 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
Basalzellkarzinom
https://clinicaltrials.gov/show/NCT02781389
Teilnehmende Zentren: • Alle am ADOREG teilnehmenden Zentren
Estimated Enrollment: 53Study Start Date: May 2016Estimated Study Completion Date: April 2020Estimated Primary Completion Date: April 2020
Basalzellkarzinom
JONASPrimary 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
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)
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)
Basalzellkarzinom
A PHASE II, SINGLE-ARMED, MULTICENTER TRIAL OF NEOADJUVANT VISMODEGIB IN PATIENTS WITH LARGE AND/OR RECURRENT BASAL CELL CARCINOMANICCI
A PHASE II, SINGLE-ARMED, MULTICENTER TRIAL
OF NEOADJUVANT VISMODEGIB IN PATIENTS
WITH LARGE AND/OR RECURRENT RESECTABLE
BASAL CELL CARCINOMA
NICCI
Martin Kaatz
SRH Wald-Klinikum Gera GmbH
Straße des Friedens 122
D-07548 Gera
247
StudienaufbauGeplante 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
Studienaufbau
249
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
251
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
Timelines
Einreichung: 16.09.2016
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 / 2019
253
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 Hornheide254
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:
E-Mail: [email protected]
Tel.: +49 (0) 365 / 828 77 58
255
256
Aufbau und Betrieb eines prospektiven
Registers zur Versorgungsforschung in der
dermatologischen Onkologie
ADOREG
Arbeitsgemeinschaft Dermatologische
Onkologie
LeitungsgruppeGarbe, Reimer,. Schadendorf,
Hansen, Weichenthal
Akademischer
ProjektbeiratUgurel, Augustin, Berking,
Gutzmer, Weichenthal
Projektleitung Basissoftware Leiter, Hansen, Plötner, Weichenthal
Wiss. Beirat
DKG DDG ADOKatalinic Enk Grabbe
beaufsichtigt
berichtet
Pharmazeutische
ProjektgruppeAlmirall Amgen, BMS, Leo,
Medac, Novartis, Roche
ADOREG-- Steuerung, Lenkung sowie Beteiligung – (Stand 06/2015)
berätformuliert
Anforde-rungen
Projekt 1
Leitung
Projekt 2
Leitung
Projekt n
Leitung
A B C D E F NG H
Zentren Definiert
Studien,
ernennt
Leitung
ber
ich
tet
berät/betreut
formuliert Anforde-
rungen
Trustcenter
Hochschule Heilbronn
Berät
Schlägt vor
ADOREG-Datenschutzkonzept
ADOREG-Zentrenstatus
• 40 aktive Zentren
• 8 weitere Verträge in Verhandlung bzw. in
Zeichnungsumlauf
• Interesse österreichischer Kliniken
Status Patienteneinschlüsse
09/2016
Entität Anzahl Patienten
MM 1.471
BCC 133
Gesamtzahl Patienten 1.632
ADOReg Rekrutierung
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
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
ADO-Reg PEM
Now
Combi-R
ADOReg
„NIS meets Register“
PemNow
PemNow
• Studienleiter: Dr. Peter Mohr, Buxtehude
• Geplante Patienten: 400
• Einschluss:
nach 1.3.2015 unter Behandlung mit
Pembrolizumab EAP oder nach Zulassung
• Gesonderte Honorierung zusätzlich zur
ADOReg-Basishonorierung
• Kontakt: [email protected]
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
27 405 201
Sponsor: Novartis
COMBI-r, eine nicht-interventionelle Studie bei Patienten mit fortgeschrittenem Melanom zur Bewertung der
Kombinationstherapie mit Dabrafenib und Trametinib in der klinischen Routine (DRB436BDE04)
Juli 2016
https://awbdb.bfarm.de/ords/f?p=101:20:::NO , BfArM: Nr. 6690
COMBI-rKombinationstherapie Dabrafenib+Trametinib in der klinischen Routine
Dokumentationszeitraum 12/2015 –
06/2019Wichtigste 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
https://awbdb.bfarm.de/ords/f?p=101:20:::NO , BfArM: Nr. 6690
COMBI-rKombinationstherapie 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.
ADOREG
Datentransfer ins ADOREG nach
ausdrücklicher und individueller
Zustimmung des Patienten
https://awbdb.bfarm.de/ords/f?p=101:20:::NO , BfArM: Nr. 6690
COMBI-rKombinationstherapie 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)
Ansprechpartner
Medical Advisor
(wissenschaftliche Fragen):
Dr. Julia Kleylein-Sohn
0911-27312118
Clinical Research Manager
(Projektmanagement und
wissenschaftliche Fragen):
Antonia Wolff
0151-218 50579
JONAS
Nicht-interventionelle Studie zur Untersuchung der
Wirksamkeit, Sicherheit und Anwendung von
Vismodegib bei lokal fortgeschrittenem und metasta-
sierten Basalzellkarzinom unter realen Bedingungen
LeitungsgruppeGarbe, Reimer,. Schadendorf,
Stiegler, Weichenthal
Akademischer
ProjektbeiratAugustin, Berking,
Gutzmer, Ugurel,
Weichenthal
Projektleitung Basissoftware Leiter, Stiegler, Thielecke, Weichenthal
Wiss. Beirat
DKG DDG ADOKatalinic Enk Grabbe
beaufsichtigt
berichtet
Pharmazeutische
ProjektgruppeAlmirall Amgen, BMS, Leo,
Medac, Novartis, Roche
ADOREG-- Steuerung, Lenkung sowie Beteiligung – (Stand 06/2015)
berätformuliert
Anforde-rungen
Projekt 1
Leitung
Projekt 2
Leitung
Projekt n
Leitung
A B C D E F NG H
Zentren Definiert
Studien,
ernennt
Leitung
ber
ich
tet
berät/betreut
formuliert Anforde-
rungen
Trustcenter
Hochschule Heilbronn
Berät
Schlägt vor
Akademische Projekte in ADOREG
• Zielsetzung
– 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)
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
• Durchführung
– Registrierung des Patienten über ADOREG
– Versand von Tumorgewebe in Form von Paraffinblock oder Schnitt-präparaten (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
TRIM (Tissue Registry in Melanoma)
TRIM (Tissue Registry in Melanoma)
Stand vom
05.09.2016:
Aktive Zentren: 12
Eingeschlossene
Patienten: 332
Anzahl der
eingesandten
Gewebeproben: 364
Kontakt:selma.ugurel@uk-
essen.de
• 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 ([email protected])
• DATENBANK: Selma Ugurel ([email protected])
TRIM (Tissue Registry in Melanoma)
Antrag
Review
Formular erarbeiten auf ADO-Reg Webseite
revidierter Antrag
Prereview
Rückfrage
Fragestellung, Datenmenge, evtl. zusätzliche Daten nötig
→ Zentrengezielt ansprechen
negativ Ablehnung
positiv
Leitungsgruppe
Zustimmung
Daten liegen vor
Aufwand/Budget
→ Finanzierung klären
Leitungsgruppe
ZustimmungODM: Daten an
Projektleiter
jageklärt
zusätzliche Datenerfassung/
Auswertung nötig
Auswertung/
Bericht
Datenerfassung,
Zentren
anfragen etc.
jaVoraus-
setzungen
vorhanden
Zeitraum?
Koautorenschaften für Zentren mit vielen Datensätzen
Patienteninfo/-EV 2.5 vom 11.8.2016
NICHT ZU VERWENDUNG ++++ ÜBERARBEITUNG FOLGT
Vielen Dank !