Klinische Trials Neuro-oncologie · Oncologie Symposium| Hoeben | 22 september 2016 10 2.1 De Novo GM: ‘Add-On STUPP’ Chemoradiation: 7 weeks RT (5/7) + TMZ 75 mg/m2/dag 6 ‘adjuvant

Klinische Trials Neuro-oncologie Targeted therapy en immunotherapie.

A. Hoeben, MD PhD Internist-Oncoloog

Oncologie Symposium| Hoeben | 22 september 2016

2

Med. Oncologist


(Potentiële) Belangenverstrengeling Geen

Disclosure belangen spreker

*

Glioblastoma

MRI T1W Gado


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.


Glioblastoma (IV): Facts.

1. RARE: NL: 400-500 /year. 2. INCURABLE 3. DIFFERENT PROGNOSTIC SUBSETS 4. HETEROGENEOUS TUMOR


‘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


7


Median Overall Survival (mOS): 14,6 months RT+TMZ vs 12,1 months RT


8 Oncologie Symposium| Hoeben | 22 september 2016

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


2.1 De Novo GM: ‘Add-On STUPP’



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%)


a) ABT-414 studie: Immunotoxin.

‘de novo’ GM harboring EGFR amplification

ABT-414: antibody-drug conjugate targets activated EGFR

12

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


ABT-414 binds to both wild-type and EGFRvIII receptors


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 vIII (de2-7) truncation sites


II

III

IV Extracellular

Kin

ase

dom

ain

-COOH

NH2

II


I II III

IV Extracellular

-NH2

-COOH

Kin

ase

dom

ain

Ligand

EGFR vIII (de2-7) truncation sites


ABT-414

ABT-414 binds to both wild-type and EGFRvIII receptors


MMAF

MMAF

MMAF

MMAF binds

Monomethylauristatin F (MMAF)


Primary endpoints: • Phase 2b: PFS • Phase 3: OS



b) Chloroquine: autophagy inhibitor.

Jutten et al. Radiat Oncol., 2013, 108, 479-483


b) Chloroquine: autophagy inhibitor.



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


Randomize in CHECKMATE-548 (RT + TMZ TMZ + nivolumab)


Vaccinatie: ICT-107


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


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


PROGNOSTIC MARKERS

PREDICTIVE MARKERS

• IDH wt/mut • hTERT

• MGMT promoter methylation

Glioblastoma: Standard of Care

3. Patient/Tumor Tailored Treatments.


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?


NON-INVASIVE GLIOBLASTOMA TESTING


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


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.


CONCLUSION: Development Clinical Trials Glioblastoma.

Documents

Klinische Trials Neuro-oncologie · Oncologie Symposium| Hoeben | 22 september 2016 10 2.1 De Novo GM: ‘Add-On STUPP’ Chemoradiation: 7 weeks RT (5/7) + TMZ 75 mg/m2/dag 6 ‘adjuvant