Brain tumour patient forum Kerrie McDonald Research development and early phase clinical trials

Research development and early phase clinical trialsDr Kerrie McDonald

Hosted by Cure Brain Cancer Foundation

Brain Tumour Research: What are we trying to achieve?

Kerrie McDonald

Affects all ages

Affects both men and women

No preventative screening measures

No effective treatment strategy

Why are brain tumours so difficult to treat?

As treatment improves and patients survive longer, we are seeing more and more tumour recurrences at distances from the initial presentation

Brain Tumours are invasive

Chemo

Chemo

Chemotherapy agents such as Temodal kill tumour cells by breaking their DNA

CHEMOSENSITIVE

Tumour cells have high levels of proteins that repair the DNA breaks caused by the chemotherapyThus: No effect

CHEMORESISTANTMGMT

High Resistance to Therapy

Multidrug resistance proteins

• All three samples are diagnosed as a high grade tumour by pathology

1. 2. 3.

High genetic variability

SURVIVALFAVOURABLE POOR

...In 2014

• On March 24 2014, the first patient with an advanced solid tumour with an IDH1 mutation was enrolled into a Phase 1 study of the compound: AG-120

• AGIOS-CELGENE AG-120 is an orally available, selective, potent inhibitor of the mutated IDH1 protein and a highly targetted first-in-class therapeutic candidate

Surgical removal of suspected GBM

Stupp ProtocolRT/TMZ

Tumour Relapse

DYNAMIC BIOBANKING

AGOG: 1016 gliomasTMAsEpidemiology Data

SLWBTB

TUMOUR GENOMICS SCREEN

CANCER DRUG SCREEN



MGMT TESTING

MGMT: Clinical Importancen=106 patients

Overall survival:

MGMT methylation: 21.7 months

MGMT unmethylation: 12.7 months

Survival Rate at 2yrs:

MGMT methylation: 46%

MGMT unmethylation: 13.8%

Hegi et al. NEJM 2005 Mar 10, 352:997-1003

Predictive impact of MGMT promoter methylation in glioblastoma of the elderly.



MGMT METHYLATEDMGMT UNMETHYLATED

VELIPARIB (ABBVIE) BMN673 (BIOMARIN) PALBOCICLIB (PFIZER) PENAO (UNSW) PENAO/DCA (UNSW) IBUDILAST (COMMERCIAL)

With/without RT GSH inhibitors MRP inhibitors

Veliparib (ABT-888)

sensitive

sensitive

resistant

resistant

17- protein “PARP inhibitor

Sensitivity” signature

0 2 4 60

0.2

0.4

0.6

0.8

1

1.2

RT alone

RT+ABT888

Radiotherapy administered (Gy)

Fra

ctio

n o

f clo

ne

s su

rviv

ed

(1

4 d

ays

)

0 1 2 4 60

0.2

0.4

0.6

0.8

1

1.2

RT alone

RT+ ABT888


Fra

ctio

n o

f clo

ne

s su

rviv

ed

(1

4 d

ays

)

0 1 2 3 40

0.2

0.4

0.6

0.8

1

1.2

RT alone

RT/ABT888


Fra

ctio

n o

f clo

ne

s su

rviv

ed

(1

4 d

ays

)

0 1 2 30

0.2

0.4

0.6

0.8

1

1.2

RT alone

RT/ABT888


Fra

ctio

n o

f clo

ne

s su

rviv

ed

(1

4 d

ays

)

Diagnosis of a GBM

MGMT

Methylated Unmethylated

Receive standard‘Stupp’ treatment

Receive veliparib 200mg BID daily and concurrent with RT and continued until toxicity or progression

Veliparib “Sensitivity Signature”

Sequencing

GBM subtyping

Exceptionalresponders

Endpoints: Primary: 12 month overall

survivalSecondary: PFS

ToxicitySignature

Phase II Veliparib design

Cancer cell metabolism is co-ordinated by the mitochondria

Glutamine

GluKGPyrAla

Pyr Pyr AcCoA

Mal

Lac

TCACycle

mitochondrion

IV II I

NAD

e-O2 2H2O

H+

H+H+

ADPATP

HKII

Glucose +ATP

ADP +G-6-P

PDH

NADH

VDAC

ANTV

H+

III

PDHK

We have made a molecule that inhibits ANT of the HKII-VDAC-ANT complex

ATP

HKII

Glucose +ATP

ADP +G-6-P

VDAC

ANT

HO2C

NH2

S

HN

OAs

OH

OH

PENAO

Time (Days)

U87

MG

Rel

ativ

e Tu

mor

vol

ume

0 2 4 6 8 10 12 140

5

10

15

20

Antitumor activityof PENAO and TMZ combination

on U87MG xenografts in Balb/C Nude mice(PENAO 13-02)

Control TD: 3.3 days

PENAO 3 mg/kg/day (SC)TMZ 2.5 mg/kg (IP)TMZ + PENAO

PENAO 3 mg/kg/day SC%T/C: 41%GD: 4.9 dSGD: 0.71TGDi: 1.71

TMZ 2.5 mg/kg/day IP%T/C: 47%GD: 3.9 dSGD: .57

TGDi: 1.57

TMZ + PENAO%T/C: 45%GD: 3.7 dSGD: 0.53TGDi: 1.53

****

Salvage Treatment

Tumour Relapse

CABARET STUDY

Looking for exceptional responders

Sequence and contrast

Exceptional Respondersresistant

IDENTIFYING TREATMENT-SENSITIVE PATIENTS

Responders

Chimeric activated receptors (CARs)

Collaborations

AGOGCOGNONSWOGCOSABCDC

Brain tumour patient forum Kerrie McDonald Research development and early phase clinical trials

Government & Nonprofit

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