Novel Targets And Strategies in

Glioblastomas

Patrick Y. Wen, M.D.

Center For Neuro-Oncology Dana Farber/Brigham and Women’s Cancer Center

Division of Neuro-Oncology, Department of Neurology Brigham and Women’s Hospitalg p

Harvard Medical School

DISCLOSURESDISCLOSURES

R h S t Ad i B d• Research Support– Amgen– Astra Zeneca

• Advisory Board– Merck– NovartisAstra Zeneca

– Boehringer Ingelheim– Esai

E li i

Novartis– Vascular Biogenic– NeOnc Inc

– Exelixis– Genentech/Roche– Geron

• Speaker– Merck– Genentech/Roche

– Medimmune– Merck

N ti

Genentech/Roche

– Novartis– Sanofi-Aventis– Vascular Biogenics

Treatment of High Grade GliomasTreatment of High-Grade Gliomas

Mil t i N O lMilestones in Neuro‐Oncology

A lApprovals

TMZ forTMZ up front

for GBMRadiotherapy

relapsed AAaccelerated

approvalGliadel wafer

Lomustine

Carmustine

Avastin forrecurrent

GBM

1970 1980 1990 2000 2010

Levin criteria:

Macdonald criteria:

MRI + steroids;

First UScommercial

MRIBrain Tumor Clinical Trial

First US commercial CT RANO

Criteria

Technology Advances

Levin criteria:CT scans

;WHO Pathology

CriteriaEndpoints Workshop ASCO

Workshop

Technology AdvancesAA=anaplastic astrocytoma; CT=computed tomography; GBM=glioblastoma multiforme; MRI=magnetic resonance imaging; RANO=Response Assessment in Neuro‐Oncology.

Ang: CVX 060, TrebananibEGF: ABT-806, Cetuximab, Nimotuzumab, Panitumumab

VEGF: Aflibercept VEGFR: Axitinib, Brivanib, Cabozantinib, Cediranib, Dasatinib, Foretinib, Lenvatinib, Nintedanib, Pazopanib, Pegdinetanib, Sorafenib, Sunitinib, VandetanibTie-2: CabozantinibFGFR: Brivanib, Lenvatinib, NintedanibCXCR4: Plerixafor

ECM

Notch

HGF: RilotumumabIL-2: Basiliximab, DaclizumabPDGFα: IMC-3G3, MEDI-575PGF: RO5323441VEGF: Bevacizumab, Ramucirumab

CXCR4: Plerixafor

N

BLOOD VESSEL

Smo

PKC

Notch

MK0752RO4929097

c-KIT: Axitinib, Cabozantinib, Imatinib,

Cilengitide

Enzastaurin

INTE

GR

IN Smo

VismodegibLDE225

ICN

PLX3391, Sunitinib, Tandutinib CXCR4:PlerixaforEGFR: Afatinib, Dacomitinib, Erlotinib, Gefitinib, Lapatinib, Ri d i t (EGFR III)

Src Bosutinib, Dasatinib, Nintedanib

HSPClient

Protein

Gli1/2

RasPI3K

RafAkt

PTENRindopepimut (EGFRvIII)HGFR/c-Met: Cabozantinib, Onartuzumab PDGFR: Axitinib, Brivanib, Crenolinib, Dasatinib, Imatinib Lenvatinib P if i

Tipifarnib

SorafenibVitespen HSP

MEK

Akt

mTOR

Imatinib, Lenvatinib, Nintedanib, Pazopanib, Sorafenib, Sunitinib, TandutinibTGF: LY2157299 Everolimus,

Sirolimus, Temsirolimus

Perifosine, PX-866

Proteosome

Client Protein

ERKTemsirolimusXL-765, GDC-0084AZD8055, CC223

Bortezomib

NUCLEUSDNA

HDAC Panobinostat, Valproic Acid, Vorinostat

VeliparibPARP

Chk Alexander, Lee et al. 2013

Outline• Issues

• New therapies and targets

• New approaches to trial design

R f L k f P i T t d M l lReasons for Lack of Progress in Targeted Molecular Therapies in Glioblastomas

• Poor models

• Blood-brain barrier

C i i f i ki• Co-activation of tyrosine kinases

• Redundant signaling pathwaysg g p y

• Spatial and temporal heterogeneity

• Failure to genetically enrich patient population

• Stem cellsStem cells

Bypassing The Blood Brain BarrierBypassing The Blood Brain Barrier

B h N l 2012 78 1268Benarroch Neurology 2012;78:1268

Connolly et al, SNO 2012

Slide courtesy of May Han, Aveo

Current DesignCurrent Design

R

Surgery

Recurrent Tumor

PKPETMRI

Blood biomarkers

PKPETMRI

Blood biomarkers

Therapy Therapy

Convection‐Enhanced DeliveryConvection‐Enhanced Delivery

Low density Lipoprotein Receptor Related Protein(LRP 1)

AngiopepTPA

(tissue plasminogen activator)

(LRP‐1)

2-Macroglobulin (MW ~ 700 kDa)

RAP

• Transports small and large molecules (> 40 ligands)

Thyroglobulin

molecules (> 40 ligands)

• One of the most expressed receptor at the surface of theLactoferrin receptor at the surface of the BBB

• Expressed on cancer cells

ß

p

• Expressed also in liver, lung and ovarian tissues

Cell Membrane

LRP-1: ~600kDa (515, 85)

ANG1005

ANG1005ANG1005

Low density ylipoprotein receptor related protein (LRP1)

ANG1005

ANG1005ANG1005

ANG1005

ANG1005

ANG1005

2013; 19(6):1567‐1576

Science 2011;344:1727

Pulse Dosing

Vivanco et al. Cancer Discovery 2012;2:458‐71

Vivanco et al. Cancer Discovery 2012;2: 458‐271

GBM Lung Cancer

Vivanco et al. Cancer Discovery 2012

Vivanco et al. Cancer Discovery 2012

Are we delivering the drugs appropriately?

• Continuous dosing versus pulse dosing

Ad i i t t t d d b f ft h th• Administer targeted drug before or after chemotherapy• NSCLC

– Solit et al CCR 2005;11:1983

– Riely JCO 2009:27;264

Targeted Molecular TherapiesTargeted Molecular Therapies

The Cancer Genome Atlas Research Network. Nature. 2008;455:1061-1068;

Stum et al. Cancer Cell 

2012;22:425‐437

Failure To Genotype Patients

Sequencing

Epigenetic Analysis

Set of activated Combinations of kinases and pathways

appropriate drugs

Ivy Foundation Early Phase Clinical Trials ConsortiumDF/HCCDF/HCCMSKCCUCLAUCSFUCSFMDACCU Utah

New Targets

• PI3KPI3K• FGFR/TACC• BRAF• CDK4CDK4• WeeI

PI3 Kinase Inhibitors

Growth Factors, etc

Ras

Raf PI3K inhibitorXL765

Mek

Erk

XL765XL147BKM120PX866

Proliferation

Erk GDC0084

Proliferation

BKM120BKM120

• Oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor belonging to the 2,6-dimorpholino pyrimidineg g , p pyderivative family

• Inhibits p110α, p110β, p110δ and p110γp , p β, p p γ

• Cross the blood-brain barrier (brain/blood ratio 2)

T k ll d il• Taken orally once daily

• Inhibits the growth of U87MG and GBM explants in vivo

39

Ivy Foundation Early Phase Clinical Trials ConsortiumA Phase II study of BKM120 for patients with recurrent glioblastoma and

activated PI3K pathway

BKM 120 T i lBKM 120 Trial

Patient Eligibility

• Activation of PI3K pathway:• Activation of PI3K pathway:

– PIK3CA/PIK3R1 mutation or

– PTEN mutation, loss of PET by FISH, or PTEN IHC negativeg

Goal

• 30 PTEN loss

• 20 PIK3CA/PIK3R1 mutants

44

20 PIK3CA/PIK3R1 mutants

Next StepsNext Steps

• Isoform specific Inhibitors– ? Beta specific isoforms better for PTEN loss? Beta specific isoforms better for PTEN loss– ? Alpha specific isoforms for PI3Ca mutants

• CombinationsBKM120 +RT+TMZ– BKM120 +RT+TMZ

– BKM120 + LDE225 (SMO inhibitor)– BKM120 + INC 280 (MET inhibitor)

Science 2012

Phase II Trial of BGJ398 (FGFR inhibitor)Phase II Trial of BGJ398 (FGFR inhibitor)

TCGATCGA 

The Cancer Genome Atlas Research Network. Nature. 2008;455:1061-1068;

PD-0332991 (CDK 4/6 inhibitor)Michaud et al: Cancer Res 2010;70:3228

Michaud et al: Cancer Res 2010;70:3228Michaud et al: Cancer Res 2010;70:3228

LY2835219 (CDK4/6 Inhibitor)Sanche Martine et alSanchez Martinez et al

h i lSanchez‐Martinez et al 

BRAF and/or MEK inhibitors for BRAFV600Emutated gliomas?mutated gliomas?

Flaherty et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600E MutationsMelanoma with BRAF V600E Mutations NEJM 2012; 2012 Nov;367(18):1694-703

A Phase II, Open-label Study in Patients with BRAF V600EMutated Rare Cancers with Several Histologies toV Mutated Rare Cancers with Several Histologies to

Investigate the Clinical Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib

Dabrafenib

Trametanib

Histologies• Anaplastic Thyroid Carcinoma

Histologies

• Biliary Tract Cancer• Diffuse Large B Cell Lymphoma• GIST• Hairy Cell Leukemia

Hi h G d Gli (GBM A l i PXA A l i• High Grade Glioma (GBM, Anaplastic PXA, Anaplastic ganglioglioma)

• Low-Grade Gliomas (PXA Ganglioglioma PilocyticLow-Grade Gliomas (PXA, Ganglioglioma, PilocyticAstrocytoma)

• Multiple Myelomap y• NSGCT/NGGCT• Small Intestine Adenocarcinoma

Plummer: Clin Cancer Res 2010;16(18); 4527–31Plummer: Clin Cancer Res 2010;16(18); 4527 31

Double strand break Single strand

break

HomologousNon-homologous Homologous

Recombination

homologous end joining (NHEJ)

Plummer: Clin Cancer Res 2010;16(18); 4527–31

I i C t t i it f TMZ d RTIncreasing Cytotoxicity of TMZ and RT

• PARP Inhibitors

– ABT 888 (ABTC; RTOG)ABT 888 (ABTC; RTOG)

• Wee1 Inhibitor

– MK1775

W 1Wee1

MK1775

G2 ArrestG2 progression and mitoticand mitotic catastrophe

Glioma Initiating Cells

Wen PY, Kesari S. N Engl J Med 2008;359:492-507

Glioma Initiating Cells

Wen PY, Kesari S. N Engl J Med 2008;359:492-507

BKM120+LDE225 In vivo data: orthotopic xenograft

f PTEN d fi iof PTEN‐deficient tumor

Mariella Gruber-Olipitz et al. Nature Med. In Press

LDE225+BKM120M

A

Combo

man

NU

MH

um

M h iMany choices; limited resources

ChallengesChallenges• Phase II trials often not predictive of positive outcome in se s o e o p ed c ve o pos ve ou co e

phase III studies– Imatinib mesylate and hydroxyureay y y– Enzastaurin– CediranibCediranib– Cintredekin Besudotox (IL13-PE38QQR)

Cilengitide– Cilengitide• More drugs and more combinations

i i d• Limited resources• Need more efficient trial designs• Need better response criteria, endpoints and more efficient

trials and design

New Clinical Trial DesignsNew Clinical Trial Designs

• Improve efficiencyImprove efficiency• Rapid elimination of ineffective regimens• Test multiple combinations simultaneouslyTest multiple combinations simultaneously• Shorter path to definitive testing

• D i• Designs• “Pick the Winner” • S l i i f h / i l• Seamless integration of phase II/III trials• Sequential Accrual Design for Phase I/II studies• Factorial Design• Adaptive Randomizationp

Adaptive Randomization StrategiesAdaptive Randomization Strategies

• Multiple arm study• Multiple arm study• Allocation of patients based on Bayesian probability of treatment

efficacyefficacy• Treatment arms with success are more likely to accrue patients• Treatment arms with poor results are dropped alternative armsTreatment arms with poor results are dropped, alternative arms

added, and accrual continues until clear evidence of superior treatment(s) emerge

A + B

A C

Ad ti R d i d “B i ” D i

A + C

A + B + CWinner

Adaptive Randomized “Bayesian” Design

Courtesy of Mark Gilbert, MD.

Trippa et al (JCO 2012; 30:3258-3263)

Trippa et al (JCO 2012;30:3258 3263)Trippa et al (JCO 2012;30:3258-3263)

Trippa et al (JCO 2012;30:3258-3263)pp ( ; )

Ideally we can have trials that evaluate multiple drugs efficiently and identify

predictive biomarkersp

Wh t M l l S b ?What Molecular Subgroups?

• EGFR amplification (45%) or mutation (20%)• PTEN loss (40%) / PIK3Ca or PIK3R1 mutations• PTEN loss (40%) / PIK3Ca or PIK3R1 mutations

(15%) • CDK4/6 amp (18%); P16/15 loss (50%)• MDM2 amplification (15%) (with intact p53MDM2 amplification (15%) (with intact p53• PDGFR amplification (13%)• Other less common subgroups

Predictive or Prognostic Biomarkers

Predictive

PrognosticPrognostic

EGFR PI3K MDM2 CDK4/6 n

+ + + + 1 (1%)

+ + + ‐ 3 (3%)

+ + ‐ + 3 (3%)

11 (12%)+ + ‐ ‐ 11 (12%)

+ ‐ + + 4 (4%)

+ ‐ + ‐ 0 (0%)0 (0%)

+ ‐ ‐ + 1 (1%)

+ ‐ ‐ ‐ 18 (20%)TCGA (all)Courtesy of 

‐ + + + 2 (2%)

‐ + + ‐ 1 (1%)

0 (0%)

Brian Alexander

‐ + ‐ + 0 (0%)

‐ + ‐ ‐ 17 (19%)

‐ ‐ + + 1 (1%)( %)

‐ ‐ + ‐ 1 (1%)

‐ ‐ ‐ + 4 (4%)

‐ ‐ ‐ ‐ 24 (26%)

41 (18) 38 (17) 13 (1) 16 (4) 91

How to prioritize overlapping classification

• Adaptive design with equal or weighted randomization will allow each subgroup to berandomization will allow each subgroup to be evaluated

BiomarkersBiomarkers

EGFR amplification/

i

Pik3Ca/PIK3R1mutations/ PTEN l

CDK4/6 amplification/P16 lmutation loss loss

+ + +

+ + 0

+ 0 +

+ 0 0

0 0 +

0 + 00 + 0

0 + +

0 0 0

Recurrent GBM

Red: EGFR AmplificationGreen: PDGFRA Amplification

PNAS 2013;110:4013;

Recurrent GBM

Reoperation and Genotype

RANDOMIZE3‐5 weeks

EGFR Amplified

40%;

MDM2Amplified

14%

PIK3Ca/R1 mutations

15%

CDK4 amplification

16%;40%; mutations

20%

14% 15%or loss of

PTEN40%

16%; P16 and 15

deletion50%40% 50%

Drug A orA+B

Drug C Drug E or Drug G or A+B or C+D E+F G+H

Survival

S i l St dSurgical Study

Possible Studies

• PI3K + MEK

• EGFR/mTOR inhibitor + Arsenic Trioxide

• etc

PNAS 2013; 110:4339‐4344

Iwanami et al: Cell Cycle 2013:12:10, 1473–1474

U87 H GBMU87 Human GBM

We are slowly making progress!We are slowly making progress!

Thank You!