klinische trials neuro-oncologie · oncologie symposium| hoeben | 22 september 2016 10 2.1 de novo...
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Klinische Trials Neuro-oncologie Targeted therapy en immunotherapie.
A. Hoeben, MD PhD Internist-Oncoloog
Oncologie Symposium| Hoeben | 22 september 2016
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Med. Oncologist
Oncologie Symposium| Hoeben | 22 september 2016
(Potentiële) Belangenverstrengeling Geen
Disclosure belangen spreker
*
Glioblastoma
MRI T1W Gado
Oncologie Symposium| Hoeben | 22 september 2016
Content – GLIOBLASTOMA
1. Introduction: Standard of Care. 2. Clinical Trials. 3. Patient Tailored Treatments: Prognostic and Predictive Markers: Non-Invasive Glioblastoma Testing. 4. Translational en Preclinical Glioblastoma Research. 5. Conclusion.
Oncologie Symposium| Hoeben | 22 september 2016
Glioblastoma (IV): Facts.
1. RARE: NL: 400-500 /year. 2. INCURABLE 3. DIFFERENT PROGNOSTIC SUBSETS 4. HETEROGENEOUS TUMOR
Oncologie Symposium| Hoeben | 22 september 2016
‘de novo’ Glioblastoma: Standard of Care
Multimodale therapy: STUPP treatment schedule. - Debulking (survival advantage over biopsy) - Stupp schema: RT + Temozolomide (vs RT)
Chemoradiation: 7 weeks RT (5/7) + TMZ 75 mg/m2/dag 6 ‘adjuvant cycles’ Temozolomide
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Stupp et al., NEJM, 2005
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Stupp et al., NEJM, 2005
Median Overall Survival (mOS): 14,6 months RT+TMZ vs 12,1 months RT
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Glioblastoma Recurrence
• No treatment options with survival benefit.
ECM
tumor cells
immune cells
endothelial cells
fibroblast
FGFR FGFR-TACC EGFRvIII Autophagy NOTCH …
VEGFR/VEGF
PD1/PDL1 CTLA4
2. Clinical Trials. Oncologie Symposium| Hoeben | 22 september 2016
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2.1 De Novo GM: ‘Add-On STUPP’
Chemoradiation: 7 weeks RT (5/7) + TMZ 75 mg/m2/dag 6 ‘adjuvant cycles’ Temozolomide
Stupp et al., NEJM, 2005
a) ABT-414: Phase 2b/3 trial. b) Chloroquine: Phase 1 trial. c) Checkmate 498/548: Nivolumab: Phase 3 trial. d) Vaccination: ICT-107: Phase 2 trial.
EGFRVIII
EGFR amplified (40%)
All GBM (100%)
EGFRVIII (25%)
EGFR overexpressed (60%)
Oncologie Symposium| Hoeben | 22 september 2016
a) ABT-414 studie: Immunotoxin.
‘de novo’ GM harboring EGFR amplification
ABT-414: antibody-drug conjugate targets activated EGFR
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Kinase domain is “off”
I II III
IV Extracellular
-NH2
-COOH
Kin
ase
dom
ain
Ligand
I
II
III
IV Extracellular
Kin
ase
dom
ain
NH2-
-COOH
Ligand
ABT-414
EGFR residues ~287-302
Oncologie Symposium| Hoeben | 22 september 2016
ABT-414 binds to both wild-type and EGFRvIII receptors
Kinase domain is “off”
I II III
IV Extracellular
-NH2
-COOH
Kin
ase
dom
ain
Ligand
I
II
III
IV Extracellular
Kin
ase
dom
ain
NH2-
-COOH
Ligand
ABT-414
EGFR residues ~287-302
EGFR vIII (de2-7) truncation sites
Oncologie Symposium| Hoeben | 22 september 2016
II
III
IV Extracellular
Kin
ase
dom
ain
-COOH
NH2
II
Kinase domain is “off”
I II III
IV Extracellular
-NH2
-COOH
Kin
ase
dom
ain
Ligand
EGFR vIII (de2-7) truncation sites
EGFR residues ~287-302
ABT-414
ABT-414 binds to both wild-type and EGFRvIII receptors
Oncologie Symposium| Hoeben | 22 september 2016
MMAF
MMAF
MMAF
MMAF binds
Monomethylauristatin F (MMAF)
Oncologie Symposium| Hoeben | 22 september 2016
Primary endpoints: • Phase 2b: PFS • Phase 3: OS
Chemoradiation: 7 weeks RT (5/7) + TMZ 75 mg/m2/dag 6 ‘adjuvant cycles’ Temozolomide
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b) Chloroquine: autophagy inhibitor.
Jutten et al. Radiat Oncol., 2013, 108, 479-483
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b) Chloroquine: autophagy inhibitor.
Chemoradiation: 7 weeks RT (5/7) + TMZ 75 mg/m2/dag 6 ‘adjuvant cycles’ Temozolomide
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c) Modulation Immune System.
Kim et al., Ann Oncol, 2016
Immune checkpoint Modulators: NIVOLUMAB
Dendritic Cell Vaccination
Immune checkpoint modulation: Checkmate 498/548: NIVOLUMAB
MGMT Un methylated Diagnosis:
supratentorial GBM
MGMT Assay
MGMT M ethylated
Clinically eligible
Clinically eligible
Randomize in CHECKMATE-498 (RT + nivolumab)
Time from surgery to start RT ≤ 42 days
Oncologie Symposium| Hoeben | 22 september 2016
Randomize in CHECKMATE-548 (RT + TMZ TMZ + nivolumab)
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Vaccinatie: ICT-107
Chemoradiation: 7 weeks RT (5/7) + TMZ 75 mg/m2/dag 6 ‘adjuvant cycles’ Temozolomide
Mature, peptide loaded dendritic cell
MHC class I
6 Antigen epitopes • MAGE-1 • AIM-2 • Gp100 • IL-13Rα2 • Her2/neu • TRO-2
DENDRITIC CELL VACCIN
DRUP: Drug Rediscovery Protocol
Fresh frozen tumor biopsy
HARTWIG MEDICAL FOUNDATION: Center for personalized Treatment’s Core Sequencing Facility
DRUP Tumor Board Oncogen; target available compound?
INCLUSION Standard of Care/other trial
yes no
Oncologie Symposium| Hoeben | 22 september 2016
2.2 Recurrent GM
22 Research meeting | Hoeben | 13 september 2016
DRUP: Drugs.
Already available:
Pembrolizumab, Nivolumab: anti-PD1 Regorafenib: multi TKI (VEGFR, KIT, BRAF, RET, PDGFR, FGFR) Vismodegib: Hedgehog Vemurafenib + Combimetinib: BRAF + MEK Trastuzumab + Pertuzumab: HER2 Panitumumab/Erlotinib: EGFR Olaparib: BRCA
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PROGNOSTIC MARKERS
PREDICTIVE MARKERS
• IDH wt/mut • hTERT
• MGMT promoter methylation
Glioblastoma: Standard of Care
3. Patient/Tumor Tailored Treatments.
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Platform of independent prognostic/predictive markers
Liquid Biopsy
Radio- genomics Radiomics MRI/
PET-MRI IHC Klinische features
Patient/Tumor Tailored Treatment
- Textures - Intensities - Shapes
- Lymphocytes (TILs) - PD-L1/PD-1 - Glioma stem-cells
(GSC) - Molecular markers
- Location and size - Enhancement - Necrosis and
edema - Multifocality - ..
Radiology Pathology Computer analysis
Non-invasive Prognostic and Predictive markers
Radiogenomics Radiomics
Liquid Biopsy Biomarker profiles?
Oncologie Symposium| Hoeben | 22 september 2016
NON-INVASIVE GLIOBLASTOMA TESTING
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4. Translational and Preclinical Research.
in vivo platform in vitro platform
IGLO: IMPROVING GLIOMA OUTCOME
Prof. Dr. Vooijs – MAASTRO lab Prof. Dr. Verhaegen – MAASTRO lab
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Orthotopic Glioblastoma Model
Yahyanejad et al., Radiotherapy and Oncology 2015 Yahyanejad et al., Oncotarget 2016
• Preclinical rationale for new treatments. • Identify essential druggable targets for TMZ resistance.
Oncologie Symposium| Hoeben | 22 september 2016
CONCLUSION: Development Clinical Trials Glioblastoma.