Date post: | 14-Dec-2015 |
Category: |
Documents |
Upload: | trevion-shireman |
View: | 213 times |
Download: | 0 times |
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