Stadler - Investigator initiated trials within the EORTC Paris 2014

Stadler - Investigator initiated trials within the EORTC Paris 2014

Investigator initiated trials within
the EORTC-Hope for the future
Rudolf Stadler
Translational Research
Sezary Syndrom
Histopathology group
Sezary Syndrom Consensus meeting
Peripheral T Cell Lymphoma
Potential Biomarker for Sézary Syndrom
© Maarten Vermeer/Wim Zoutman
European Multicenter study of the EORTC CLTF
© Maarten Vermeer/Wim Zoutman
Results of the Genexpression (GE)
• Diagnostic significance
- At least 2 markers are necessary to diagnose SS (100%)
- Specifity: 100%
© Maarten Vermeer/Wim Zoutman
12./13.05.2011 &
03./04.11.2011
M
a
n
n
h
e
i
m
Birgit Arheiliger, Minden
Chalid Assaf, Krefeld
Martine Bagot, Paris
Maxime Batistella, Paris
Patty Jansen, Leiden
Werner Kempf, Zürich
Robert Knobler, Wien
Nicolas Ortonne, Paris
Pietro Quaglino, Turin
Marco Santucci, Florenz
Maarten H. Vermeer, Leiden
Rein Willemze, Leiden
E
O
R
T
C
C
L
T
F
Nina Booken
Moritz Felcht
Cyril Géraud
Sergij Goerdt
Jan Nicolay
Sayran Arif-Said
Anneliese Pfisterer
Inge Röhmer
Christel Weiß (Statistik)
Mannheim
H&E
CD3
CD4
CD7 Verlust = <50% Expression
Minden 3 (SS)
H&E
CD3
CD7 Verlust (<50%)
PD-1 Expression >50%
Turin 2 (SS)
Deep dermal Infiltrates are associated with a
worse prognosis
survival probability
Kaplan-Meier - Overall Survival for SS
with or without deep dermal infiltrate
1,00
p=0.0175
SS without
0,75
censored
0,50
SS with
0,25
censored
0,00
0
25
50
75
100
survival time - months
125
150
Summary
• The Histopathology of SS is characterized by
•
Epidermotropism (Expression , Pautrier
Microabszesses)
•
Increased Atypical Lymphocytes (cerebriform, blastär)
•
CD7 loss
•
PD-1 und MUM-1 Expression
•
Less CD8+ cells
•
Increased proliferation
• Negative prognostic Marker for SS are diffuse and deep
dermal infiltrates
Goals of Therapy in Patients with
CTCL in 2014
Hope to Cure or increase DFS
Durable Remission lasting > 1yr
PR and decreased symptoms
Stabilize to prevent progression
Recognize and treat infections
Avoid immunosuppression and toxicity
Therapeutic Options for Cutaneous T-cell
Lymphoma, 2014
•
•
•
•
Topical/skin directed therapy
– Topical steroids, , phototherapy (UVB/PUVA), PDT, radiation treatment,
imiquimod
Systemic therapy
– Biologics, targeted therapy:
• Photopheresis, interferon, retinoid (bexarotene), fusion protein/toxin
(denileukin diftitox*), alemtuzumab**
•*FDA approved
– HDAC inhibitors: vorinostat*, romidepsin*
•** taken off the market
– Chemotherapeutics:
• MTX, lipo. doxorubicin, gemcitabine, etoposid, pentostatin, combinations,
pralatrexat (approved for PTCL*)
Combination therapies
– Topical and photo therapy, topical and systemic, systemic + systemic
Investigative therapy
– Monoclonal antibodies (e.g., CD30, CCR4)
- Kinase inhibitors
– TLRA (e.g., CpG, resiquimod)
- Vaccination strategies
– Improved chemotherapeutic, misc.
- Allo transplantation
Disappointing results or not further developed
- Forodesine, Zanolimumab
Efficacy of Systemic Therapy in CTCL
Drug
Indication
Study
N
ORR
DOR
Bexarotene
CTCL all
stages
Pivotal
62
32%
5+ mo
Romidepsin
CTCL and
systemic
therapy
Pivotal
96
34%
15 mo
Supportive
71
35%
11 mo
CTCL
Pivotal
74
30%
6+ mo
Supportive
33
24%
4 mo
Pivotal
71
30%
4 mo
Vorinostat
Denileukin
diftitox
CTCL with
CD25
expression
Cutaneous Lymphoma as an orphan disease
for drug development 10 years ago
Drugs screened:
HDAC´S
Forodesine
Proteasome inhibitor
Zanolinumab
Alemtuzumab
21011 Bexarotene +- PUVA
21012 Liposomal encapsulated
Doxorubicin
JCO 2012
Cutaneous T-Cell Lymphoma
Stage
IA
Mean Survival
T1
N0 M0
T2
IIA
T1-2 N1 M0
10.0 years
IIB
T3
N0-1 M0
2.9 years
III
T4
N0-1 M0
3.6 – 4.6 years
IVA
T1-4
T1-4
N2-3 M0
N0-3 M1
12.1 –
25% may progress
12.8 years to advanced disease
with a median
survival < 4 years !
IB
IVB
N0 M0
32 J. not reached
13 month
13 month
J.J. Scarisbrick et al
BJD 2014
EORTC CLTF platform
Trial 1 endpoint
TTR/TTP
Trial 2 endpoint
ORR
Observation
Trial 3 endpoint
ORR
Relapse / progression
and appropriate for SDT
Relapse/progression
appropriate for SDT
CR/PR
Relapse/progression
after 6 months and
inappropriate for SDT
~30-40%
Debulking 1 +
additional
therapy 1
Relapse/progression
inappropriate for SDT
Maintenance
Relapse/progression
within 6 months and
inappropriate for SDT
Debulking 1
2
Vorinostat &
Vidaza
Debulking agent 2 plus
additional therapy 2
SD/PD
1
Revlimid
~60-70%
Phase III: 100 pts
Vorinostat &
Vidaza
EBMT RISCT Protocol
3
EORTC Study:
Lenalidomide maintenance postdebulking
in advanced CTCL
Debulking with
gemcitabine
R
or
liposomal doxorubicin
Lenalidomide 25mg po
D1-21, q 4 w
until PD or untolerable∗
Observation
Advanced stage MF (stage IIB-IV)
Or Sezary Syndrome
∗ for max 560 days
Primary endpoint: PFS
EORTC 21081: A phase III study of lenalidomide
maintenance after debulking therapy in patients with
advanced cutaneous T-cell lymphoma.
The CTCL Platform
• Reasons for failure:
- Complicated study design for the
maintanance study
- Prolongation due to regulatory affairs
- Drug development was stopped
- No aggreement within the BMT group
on one protocol
Arguments for EORTC studies in
cooperation with academic medicine
and industry
EORTC as a label for independance and reputation
in clinical research
EORTC infrastructure with specialized and
experienced expert in clinical studies
EORTC as a clinical integrative research platform
for Pan- European medicine
EORTC as a strong inter-disciplinary network in oncology
Problems for EORTC studies in cooperation
with academic medicine and industry
New drug developments are performed by
pharmaceutical companies under their control and
leadership: Data ownership
Companies do not recognize the additional value of
being asscociated with EORTC
Clinical research is financed directly by clinical
studies provided by pharma industry
Individual centers have a higher profit margin
EORTC‘s reputation is of controversial value
Problems for EORTC studies in cooperation
with academic medicine and industry
How to solve the problems
- Establishing a clinical study group
- Defining new targets for therapy based on
translational research
- Involvement in early drug development
- Performing small and effective Phase I and
II studies
- Performing studies in a given time frame
- Fund raising
Nature Review 2014
Nature Review 2014
Stage
I
II
III
CD4+
IV
CD4+
CD8+
New target structures
CD8+
Receptors eg. CCR4,6 , singalling pathways: STAT3 ,Notch, NFκΒ,
PI3K
Cell surface markers
CD5, CD7,
CTLA4,PD1,PDL1, KIR,
CD26, CD30
cytokines
Th1 (IL-2, IL-12, IFN-γ), Th2 (IL-4, IL-13), Th17 (IL-17)
IL-5, IL-10
Sézary Syndrome and MF Proliferate out
of Specific T-Cell Fractions
SS
CD45RO+
CLA+,CD27,CCR6,CCR10
Central Memory TCM
MF
CD45RO+ ,CCR7-,L-selectin-/
CD27lo ,CCR8
CLA+,CCR4
Resident Memory TEM
Campbell et al., Blood 2010
Precision therapy for lymphoma – current
state and future directions
A.M. Intlekofer and Anas Younes Nat. Rev. Clin. Oncol. 2014
MLN8237 (alisertib): Overview
• Investigational small molecule
inhibitor of Aurora A kinase
(AAK)
– AAK regulates aspects of cell
mitosis
– Administered orally
– Clinical studies are
evaluating dosing schedules
and pharmacodynamics
– Phase 1 and 2 trials are
ongoing in patients with solid
tumors and hematologic
malignancies
– Phase 3 trial initiated in
relapsed/refractory peripheral
T-cell lymphoma (PTCL)
31
The Blockade of Immune Checkpoints
in Cancer Immunotherapy
Pardoll DM Nat Rev Cancer 2012
PD-1-Expression bei MF und SS
Lymphomtyp
N=
>50%
T-Zellen
PD-1 %
11-50%
Sezary Syndrom
27
24
89%
1 Fall
Mycosis
60
fungoides
MF patch/ plaque 30
8
13%
4 Fälle
4
13%
2 Fälle
MF Tumor
MF
erythrodermic
3
1
14%
12%
1 Fall
1 Fall
22
8
Cetinözman F. et al., Arch Dermatol 2012
The Role of JAKS and STATS
Tofacitinib
NEJM 2013
STAT3 as a Therapeutic Target
JCO 2014
JCO accepted for publication
TLR Agonists
TLR 7/8
Resiquimod 0.06% Gel
Rook et al SID 2013
Th Roger et al 2011
Targeting B-cell Receptor
Signaling
A. Wiestner JCO 2013
Study Scenario in Europe
Study medication provided by pharmaindustry,
defined target by translational research
Countries: 9 European countries
Phase II FS approximately 545.000 Euro incl. PT
CM approximately 270.000 Euro incl. PT
30-50 patients, 2 year recruting period, 1year follow up
Electronic CRF
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