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 clinicotranslational components
-
Submit Multi-PI Grant applications.
The Algorithm
ERCC 1 Expression
(ERCC1 mRNA)
Platinum withheld
Treatment with Platinum
RRM1 Expression
High
Docetaxel
+
Navelbine
Low
Gemcitabine
RRM1 Expression
High
Low
Carboplatin
+
+
Docetaxel
Docetaxel
Carboplatin
+
Gemcitabine
Overall Survival: PT vs. ST
1
Censored
Standard
Personalized
Probability of Overall Survival
0.9
0.8
0.7
Median OS (95% CI)
Standard: 8.1 (6.1-11.4)
Personalized: 12.3 (10.1-17.1)
0.6
0.5
0.4
0.3
0.2
6.2
0.1
0
0
No. at Risk
Standard
125
Personalized 53
6
12
18
24
30
36
42
48
14
9
10
8
6
7
Month Posttranplant
74
42
50
26
32
19
20
16
18
12
Simon et al. IASLC presentation, WCLC, 09.
The Phase III Design
Randomization (2 :1)
Customization Arm
Chemotherapy assigned
according to the MADe IT
Algorithm
Non-Customization Arm
Gemcitabine & Carboplatin
iMAP: Tailoring for EGFR MutNon-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 + DE
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 Trial
Elderly and Poor Performance Status Individualized
Chemotherapy Trial
2:1 Randomization
Individualized Arm
Control Arm
Squamous Cell Carcinoma
Treatment based on Investigators’ Preference
Ye
s
E1 low
R1 high
E1 high
R1 low
Carboplatin Gemcitabine
No
E1 low
R1 low
E1 high
R1 high
Carbo/Gem
Docetaxel/
Paclitaxel
EGFR Mut +
Yes
Off Study
No
E1 low
TS high
Carboplatin
E1 high
TS low
Pemetrexed
E1 low
TS low
Carbo/Pem
E1 high
TS high
RRM1 low
Gemcitabine
PIs : G. Simon & G. Scagliotti
Medical University of South Carolina (Hollings Cancer Center) & University of Torino
RRM1 high
Docetaxel
Lung Cancer Research Landscape –
MoA Group & Phase
Danusertib I
Other
tipifarnib I
MORab-009 A
Cancer Stem Cell Targeting (PPAR, Hedgehog)
Obatoclax
JNJ-26854165
ARQ-621
Mitotic/Topoisomerase Inhibitors
ARC-100
AMP-001
PF-2341066
GDC0449
Camptothecin
Lip. Paclitaxel
BI-6727
Intetumumab A
MetMab
BMS833923
AMG-386
= 2nd-line
IMGN-242
ARQ197
Vascular Disrupting Agents
IPI-926
PEG-Irinotecan
Reolysin
BNC-105
= 1st and 2nd line
Apricoxib
CS-7017
Cositecan
Irvalec (Custirsen)
CYT-997
= 3rd-line
ARRAY520
Crinobulin
Retaspimycin
Cilengitide
Ixabepilone
ABT-751
VEGF Inhibitors
= Undeclared
AMG102
KOS-1584
Zibotentan
Fosbretabulin (CA4P) A Lexatumumab
BI-2536
Eribulin
= SCLC
AV-951 I
bexarotene
ANG-615 A Bavituximab
LCL-161
Apoptosis Agonist
E-7080 I
Amrubicin
ADH-1 (Exherin)
XL-647 I
AVE-8062
= TKI
ISIS-23722
I PF-00299804
Paclitaxel
NPI-2358
Ramucirumab A
rebimastat
Dulanermin (AMG-951)
I Cediranib
= Antibody
Auristatin PE
I Motesanib (Albumin B.)
ABT-869 I
LY573636
Mapatumumab
A
I Pazopanib
I Sunitinib
ASA404
Topotecan
XL-184 I
YM-155
DNA Repair Inhibitors
AEG35156
I Axitinib
I BMS-690514
Vinorelbine/ Vinblastine
Apomab A
CT-322
ABT-888
Neratinib I
Kahalalide F
I Sorafenib
Paclitaxel
Aflibercept
Zometa
AMG655
AG-014699
BMS-690514 I
Vandetanib I
Etoposide
MP-470
Panitumumab A BIBW2992
EGFR Inhibitors
Bevacizumab A
BSI-201
Irinotecan
I Bosutinib
Nimotuzumab A Neratinib I
KX2-391
Docetaxel
Gefitinib I
I Erlotinib
I Dasatinib (Sprycel)
PF-00299804 I
Cetuximab A
Pertuzumab A Matuzumab
AZD-0530
Approved/Launched
Src Inhibitors
BIBF-1120 I
Everolimus (RAD-001)
Cisplatin
Brivanib I
XL-999
Sirolimus (Rapamycin)
AV-370
Figitumumab A
Liposomal Cisplatin
FGFR Inhibitors
Temsirolimus
(CCI-779)
Gemcitabine
(CP-751871)
TKI-258 I
Carboplatin
F-50035 A
Enzostaurin
XL-281
Pemetrexed
Ifosfamide
Talactoferrin
Registered
Deforolimus
(AP23573)
A Cixutumumab
Sapacitabine
Lucanix
AVE-1642
Imprime PGG
AZD-6244
PX-866
PI3K. mTOR, AKT,
NOV-002
A AMG-479
Mage-A3
Vorinostat
PicoPt
BHB022
Stimuvax
MKC-1
MAPK/ERK Inhibitors
I XL-184
OSI-027
Oblimersen
Temozolomide
Retaspimycin Phase III
A R-1507
GI4000
BEZ-235 / BTGT226 / BKM
CimaVax EGF
Etinostat
Panobinostat
AT-101
OSI-906
Tremelimumab
AZD-8055
Decitabine
IGFR Inhibitors
obatoclax
PF-3512676
IMO-2055
Pralatrexate
ARRY-886
XL-228
ABT-263
(agatolimod)
belinostat
Glufosfamide
EC-145
AUY922
Phase II
Vical-2 vaccine
MDX-1105
SNX5542
V-935
GVAX
Immunostimulants/Vaccines
MGCD-0103
VX-001
AS-1411
V-930
Protein Degradation
ABT-263
A Naptumomab
= IV & PO
= PO
= IV
= 1st-line
I
A
Source: Compiled by Neeta Somaiah & George Simon.
Vinorelbine (emulsion)
Phase I
Antimetabolites
Bcl-2 Inhibitors
Alkylating Agents
New drugs that will be available at
MUSC through Clinical Trials
OSI 906
Afatinib
Vorinostat/radiation
BKM120
LBH589/Sorafenib
Documitinib
MM121 (HER-3i)
GP96 Vaccine
MAGE A3 Vaccine
Crizotinib
LY2523355 (EG5i)
Pazopanib
MetMab +Erlotinib
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 secondline 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