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

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Presentation on theme: "A Road-Map to Integrated Biomarker Studies George R. Simon, MD Hollings Cancer Center Medical University of South Carolina Charleston, SC."— Presentation transcript:

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

2 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

3 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

4 Stepwise Approach…. 3. Grant Applications.. - Grants where synergistic collaborations exist (1-2 Years)

5 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.


7 The Algorithm ERCC 1 Expression (ERCC1 mRNA) Platinum withheldTreatment with Platinum RRM1 Expression Docetaxel Gemcitabine Navelbine Docetaxel Carboplatin Docetaxel + +++ RRM1 Expression Carboplatin Gemcitabine High Low High Low

8 Overall Survival: PT vs. ST Simon et al. IASLC presentation, WCLC, 09.

9 The Phase III Design Randomization (2 :1) Customization ArmNon-Customization Arm Chemotherapy assigned according to the MADe IT Algorithm Gemcitabine & Carboplatin

10 iMAP: Tailoring for EGFR Mut- Non-Sq Squam ERCC1+D + P D + V  ERRM1+ ERCC1+D + G RRM1- ERCC1-C + P + BC + PC + D  ERRM1+ ERCC1-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

11 EPIC Trial Elderly and Poor Performance Status Individualized Chemotherapy Trial 2:1 Randomization Individualized ArmControl Arm Squamous Cell Carcinoma Ye s No EGFR Mut + Off Study E1 low R1 high E1 high R1 low E1 low R1 low E1 high R1 high CarboplatinGemcitabineCarbo/GemDocetaxel/ Paclitaxel E1 low TS high E1 high TS low E1 low TS low E1 high TS high CarboplatinPemetrexedCarbo/Pem Yes No RRM1 lowRRM1 high GemcitabineDocetaxel Treatment based on Investigators’ Preference PIs : G. Simon & G. Scagliotti Medical University of South Carolina (Hollings Cancer Center) & University of Torino

12 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 InhibitorsVEGF Inhibitors Fosbretabulin (CA4P) ABT-751 ANG-615 NPI-2358 ASA404 Aflibercept I Vandetanib A Ramucirumab I XL-647 I AV-951 CT-322 A Bevacizumab Ixabepilone BI-2536 ARRAY520 Vorinostat Retaspimycin Etinostat AUY922 Everolimus (RAD-001) Sirolimus (Rapamycin) Temsirolimus (CCI-779) Enzostaurin Deforolimus (AP23573) AZD-6244PX-866 OSI-027 AZD-8055 I XL-184 Figitumumab (CP-751871) AVE-1642 A Cixutumumab A AMG-479 OSI-906 = IV & PO = PO = IV = 1 st -line = 2 nd -line = 1 st and 2 nd line = 3 rd -line = Undeclared PF-2341066 MetMab BHB022 Dulanermin (AMG-951) A Mapatumumab A Apomab AMG655 LCL-161 YM-155 I Dasatinib (Sprycel) AZD-0530 KX2-391 I Brivanib AV-370 I TKI-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 I BMS-690514 Cisplatin Carboplatin Ifosfamide A Cetuximab I Erlotinib Docetaxel Antimetabolites = SCLC Etoposide Gemcitabine Irinotecan Paclitaxel Pemetrexed Vinorelbine/ Vinblastine Paclitaxel (Albumin B.) Liposomal Cisplatin Panobinostat GDC0449 AMG102 AEG35156 A Bavituximab I Cediranib A Panitumumab A Nimotuzumab Matuzumab Gefitinib I Sunitinib Sorafenib I Axitinib I Motesanib A R-1507 XL-228 MKC-1 Oblimersen Cilengitide Talactoferrin Sapacitabine Reolysin Irvalec (Custirsen) Mage-A3 Stimuvax PF-3512676 (agatolimod) Tremelimumab Imprime PGG GVAX CimaVax EGF AVE-8062 Pralatrexate ARQ197 Apricoxib I ABT-869 ARRY-886 ARC-100 AS-1411 BI-6727 Decitabine Cositecan Glufosfamide Eribulin I Bosutinib Kahalalide F IMO-2055 EC-145 A F-50035 GI4000 KOS-1584 A Lexatumumab ARQ-621 Lip. Paclitaxel Camptothecin ISIS-23722 PEG-Irinotecan MDX-1105 A Intetumumab I E-7080 AMP-001 IMGN-242 I Danusertib JNJ-26854165 Vical-2 vaccine A I tipifarnib Pertuzumab I Neratinib A Naptumomab MGCD-0103 A MORab-009 MP-470 V-930 VX-001 Vinorelbine (emulsion) V-935 Crinobulin Registered XL-999 I BIBF-1120 I XL-184 I I BMS-690514 I Pazopanib SNX5542 Temozolomide PicoPt Obatoclax AT-101 Zibotentan Amrubicin PF-00299804 I Topotecan ABT-263 I Neratinib LY573636 BEZ-235 / BTGT226 / BKM Bcl-2 Inhibitors obatoclax A I BSI-201 Auristatin PE ADH-1 (Exherin) I = TKI A = Antibody Zometa bexarotene Lucanix NOV-002 belinostat CYT-997 AMG-386 Retaspimycin ABT-263 BNC-105 rebimastat

13 New drugs that will be available at MUSC through Clinical Trials OSI 906 GP96 Vaccine Afatinib MAGE A3 Vaccine Vorinostat/radiation Crizotinib BKM120LY2523355 (EG5i) LBH589/SorafenibPazopanib DocumitinibMetMab +Erlotinib MM121 (HER-3i)Cetuximab

14 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.

15 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.

16 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

17 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

18 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

19 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?

20 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

21 Questions

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