A Road-Map to Integrated Biomarker Studies George R. Simon, MD Hollings Cancer Center Medical University of South Carolina Charleston, SC.

A Road-Map to Integrated Biomarker Studies

George R. Simon, MD

Hollings Cancer Center

Medical University of South Carolina

Charleston, SC

Stepwise Approach..

1. Clinical trials Portfolio

- Obtain funding for and open a series of investigator initiated studies

- Open industry funded studies with novel compounds with against novel targets

Stepwise Approach..

2. Create a platform for translational and basic research among investigators with synergistic interests

- Form Research Streams

- Monthly Thoracic Research Group Meetings

- Monthly Thoracic Working Group Meetings

- Weekly Thoracic Research In Progress Meetings

- Thoracic Retreats – 2011- Dr. Paul Bunn

Stepwise Approach….

3. Grant Applications..

- Grants where synergistic collaborations exist (1-2 Years)

Measures of Success..

- Demonstrate that we can enroll patients on clinical trials and complete and publish these studies.

- Successful funding of grants with clinico-translational components

- Submit Multi-PI Grant applications.

The Algorithm

ERCC 1 Expression

(ERCC1 mRNA)

Platinum withheld

Treatment with Platinum

RRM1 Expression

Docetaxel

Gemcitabine

Navelbine

Docetaxel

Carboplatin

Docetaxel+ + + +

RRM1 Expression

Carboplatin

Gemcitabine

High Low High Low

Overall Survival: PT vs. ST

0 6 12 18 24 30 36 42 480

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

5.96.2

Month Posttranplant

Pro

ba

bili

ty o

f Ove

rall

Su

rviv

al

No. at RiskStandard 125 74 50 32 20 18 14 10 6Personalized 53 42 26 19 16 12 9 8 7

CensoredStandardPersonalized

Median OS (95% CI)Standard: 8.1 (6.1-11.4)Personalized: 12.3 (10.1-17.1)

Simon et al. IASLC presentation, WCLC, 09.

The Phase III Design

Randomization (2 :1)

Customization Arm

Non-Customization Arm

Chemotherapy assigned according to the MADe IT Algorithm

Gemcitabine & Carboplatin

iMAP: Tailoring for EGFR Mut-

Non-Sq Non-Sq Squam

ERCC1+ D + P D + P D + V E RRM1+

ERCC1+ D + G D + G D + G RRM1-

ERCC1- C + P + B C + P C + DE RRM1+

ERCC1- C + G C + G C + G RRM1-

Bev+ Bev-

Letter in bold indicates maintenance drug. D = Docetaxel; P = Pemetrexed;

G = Gemcitabine; V = Vinorelbine; C = Carboplatin; B = Bevacizumab; E = Erlotinib

EPIC TrialElderly and Poor Performance Status Individualized Chemotherapy Trial

2:1 Randomization

Individualized Arm Control Arm

Squamous Cell Carcinoma

Yes

No EGFR Mut + Off Study

E1 lowR1 high

E1 highR1 low

E1 lowR1 low

E1 highR1 high

Carboplatin Gemcitabine Carbo/Gem Docetaxel/Paclitaxel

E1 lowTS high

E1 highTS low

E1 lowTS low

E1 highTS high

Carboplatin Pemetrexed Carbo/Pem

Yes

No

RRM1 low RRM1 high

Gemcitabine Docetaxel

Treatment based on Investigators’ Preference

PIs : G. Simon & G. ScagliottiMedical University of South Carolina (Hollings Cancer Center) & University of Torino

Lung Cancer Research Landscape – MoA Group & Phase

Source: Compiled by Neeta Somaiah & George Simon.

Approved/Launched Src Inhibitors

PI3K. mTOR, AKT, MAPK/ERK Inhibitors

Apoptosis Agonist

FGFR Inhibitors

DNA Repair Inhibitors

Vascular Disrupting Agents

Mitotic/Topoisomerase Inhibitors

Other

Alkylating Agents

Protein Degradation

IGFR Inhibitors

Immunostimulants/Vaccines

EGFR Inhibitors

VEGF InhibitorsFosbretabulin (CA4P)

ABT-751

ANG-615

NPI-2358

ASA404

AfliberceptIVandetanib

ARamucirumabIXL-647

IAV-951

CT-322

ABevacizumab

Ixabepilone

BI-2536

ARRAY520

Vorinostat

Retaspimycin

Etinostat

AUY922

Everolimus (RAD-001)

Sirolimus (Rapamycin)

Temsirolimus (CCI-779)

Enzostaurin

Deforolimus (AP23573)

AZD-6244 PX-866

OSI-027

AZD-8055

I XL-184

Figitumumab (CP-751871)

AVE-1642A Cixutumumab

A AMG-479

OSI-906

= IV & PO

= PO

= IV

= 1st-line

= 2nd-line

= 1st and 2nd line

= 3rd-line

= Undeclared

PF-2341066

MetMab

BHB022

Dulanermin (AMG-951)

A Mapatumumab

AApomabAMG655

LCL-161

YM-155

I Dasatinib (Sprycel)AZD-0530

KX2-391

IBrivanibAV-370

ITKI-258

AG-014699

ABT-888

CS-7017

Phase III

Phase II

Phase I

Cancer Stem Cell Targeting (PPAR, Hedgehog)

IPI-926

XL-281

BMS833923

BIBW2992

I PF-00299804

IBMS-690514

Cisplatin

CarboplatinIfosfamide

ACetuximabI Erlotinib

Docetaxel

Antimetabolites

= SCLC

Etoposide

Gemcitabine

Irinotecan

Paclitaxel

Pemetrexed

Vinorelbine/ Vinblastine

Paclitaxel (Albumin B.)

Liposomal Cisplatin

Panobinostat

GDC0449

AMG102

AEG35156

A Bavituximab

I Cediranib

APanitumumabANimotuzumab

Matuzumab

Gefitinib

I Sunitinib

SorafenibI Axitinib

I Motesanib

A R-1507

XL-228

MKC-1Oblimersen

Cilengitide

TalactoferrinSapacitabine

Reolysin

Irvalec (Custirsen)

Mage-A3Stimuvax

PF-3512676 (agatolimod)

Tremelimumab

Imprime PGG

GVAX

CimaVax EGF

AVE-8062

Pralatrexate

ARQ197

Apricoxib

IABT-869

ARRY-886

ARC-100

AS-1411

BI-6727

Decitabine

Cositecan

Glufosfamide

Eribulin

I Bosutinib

Kahalalide F

IMO-2055

EC-145

AF-50035

GI4000

KOS-1584A Lexatumumab

ARQ-621

Lip. PaclitaxelCamptothecin

ISIS-23722

PEG-Irinotecan

MDX-1105

AIntetumumab

IE-7080

AMP-001

IMGN-242

IDanusertib

JNJ-26854165

Vical-2 vaccine

A

Itipifarnib

Pertuzumab

INeratinib

A Naptumomab

MGCD-0103

AMORab-009

MP-470

V-930VX-001

Vinorelbine (emulsion)

V-935

Crinobulin

Registered

XL-999

IBIBF-1120

I

XL-184 II BMS-690514

I Pazopanib

SNX5542

TemozolomidePicoPt

Obatoclax

AT-101

Zibotentan

Amrubicin

PF-00299804 I

Topotecan

ABT-263

INeratinib

LY573636

BEZ-235 / BTGT226 / BKM

Bcl-2 Inhibitors

obatoclax

A

I

BSI-201

Auristatin PE

ADH-1 (Exherin)I = TKIA = Antibody

Zometa

bexarotene

LucanixNOV-002

belinostat

CYT-997

AMG-386

Retaspimycin

ABT-263

BNC-105

rebimastat

New drugs that will be available at MUSC through Clinical Trials

OSI 906 GP96 Vaccine

Afatinib MAGE A3 Vaccine

Vorinostat/radiation Crizotinib

BKM120 LY2523355 (EG5i)

LBH589/Sorafenib Pazopanib

Documitinib MetMab +Erlotinib

MM121 (HER-3i) Cetuximab

Proposed Road Map

- Design definitively powered clinical trials which will answer a relevant clinical question

- Studies should be investigator initiated and designed in house

- Funded either by internal or external sources or multiple sources.

Proposed Road Map (Contd)

- Build in correlative analyses and analyses of patient specimens in individual PI labs.

- Integrate Novel Analytic Platforms in these studies.

- Components of the clinical trial could be a specific aims in individual PI grant applications.

Road Map (contd)

One or two studies each for Patients Populations in substantial numbers at HCC

One study each could be done for Breast, GI, Lung, GU, Malignant Heme etc

Clinicians for the clinical programs can help define the clinical question

Road Map (contd)….

Basic scientists work with the clinicians to help with developing the correlative studies especially building on the research focus of the individual PI labs

This demonstrates collaborations between the programs and disease focus groups

Road Map (contd)….

In thoracic, we now have investigator-initiated or Novel targeted therapy trials for all stages of NSCLC and SCLC

We hope to now focus on more definitive executable clinical trials which will answer a question of relevance to patient care

Example of a study with integrated components…

Clinical Question: Does the addition of metformin to standard of care in the second-line or third-line setting improve survival over standard of care alone

Is activity of metformin augmented by mTOR inhibitors?

Example of a study with integrated components…

Correlative studies: Ask a series of questions. Is response to metformin affected by LKB1 mutations in LKB1, p53, AKT, mTOR, EMT status and a variety of other molecules..

Potentially use the photonic nanocrystal platform to be able to check multiple markers

Questions