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A Road-Map to Integrated Biomarker Studies

A Road-Map to Integrated Biomarker Studies. George R. Simon, MD Hollings Cancer Center Medical University of South Carolina Charleston, SC. Stepwise Approach. Clinical trials Portfolio - Obtain funding for and open a series of investigator initiated studies

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A Road-Map to Integrated Biomarker Studies

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  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.. • 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.

  6. The Algorithm ERCC 1 Expression (ERCC1 mRNA) Platinum withheld Treatment with Platinum RRM1 Expression RRM1 Expression High High Low Low Gemcitabine Docetaxel Carboplatin Carboplatin + + + + Docetaxel Gemcitabine Docetaxel Navelbine

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

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

  9. iMAP: Tailoring for EGFR Mut- Letter in bold indicates maintenance drug. D = Docetaxel; P = Pemetrexed; G = Gemcitabine; V = Vinorelbine; C = Carboplatin; B = Bevacizumab; E = Erlotinib

  10. EPIC TrialElderly and Poor Performance Status Individualized Chemotherapy Trial 2:1 Randomization IndividualizedArm ControlArm SquamousCell Carcinoma Treatment based on Investigators’ Preference Yes No EGFR Mut + Off Study Yes E1 low R1 high E1 high R1 low E1 low R1 low E1 high R1 high No Carboplatin Gemcitabine Carbo/Gem Docetaxel/ Paclitaxel E1 high TS high E1 low TS high E1 high TS low E1 low TS low Carboplatin Pemetrexed Carbo/Pem RRM1 low RRM1 high PIs : G. Simon & G. Scagliotti Medical University of South Carolina (Hollings Cancer Center) & University of Torino Gemcitabine Docetaxel

  11. Protein Degradation VEGF Inhibitors Cancer Stem Cell Targeting (PPAR, Hedgehog) Antimetabolites Src Inhibitors PI3K. mTOR, AKT, MAPK/ERK Inhibitors Apoptosis Agonist FGFR Inhibitors DNA Repair Inhibitors EGFR Inhibitors Mitotic/Topoisomerase Inhibitors Other Alkylating Agents Bcl-2 Inhibitors IGFR Inhibitors Vascular Disrupting Agents Immunostimulants/Vaccines Lung Cancer Research Landscape – MoA Group & Phase Danusertib I = IV & PO Vinorelbine (emulsion) tipifarnib I MORab-009 = PO A Obatoclax JNJ-26854165 ARQ-621 = IV ARC-100 AMP-001 PF-2341066 GDC0449 = 1st-line Camptothecin Lip. Paclitaxel BI-6727 Intetumumab A MetMab BMS833923 AMG-386 = 2nd-line IMGN-242 ARQ197 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 = Undeclared AMG102 KOS-1584 Zibotentan Lexatumumab Fosbretabulin (CA4P) A BI-2536 Eribulin = SCLC AV-951 bexarotene Bavituximab ANG-615 LCL-161 I A E-7080 Amrubicin ADH-1 (Exherin) XL-647 I AVE-8062 I = TKI ISIS-23722 I PF-00299804 Paclitaxel (Albumin B.) I NPI-2358 Ramucirumab rebimastat A Dulanermin (AMG-951) Cediranib = Antibody Auristatin PE A Motesanib I ABT-869 I LY573636 I Mapatumumab Pazopanib A Sunitinib ASA404 Topotecan I XL-184 YM-155 I I AEG35156 Axitinib BMS-690514 Vinorelbine/ Vinblastine Apomab CT-322 I I ABT-888 Neratinib A I Kahalalide F Sorafenib Paclitaxel Aflibercept Zometa I AMG655 AG-014699 BMS-690514 I Vandetanib Etoposide MP-470 I Panitumumab Bevacizumab BSI-201 BIBW2992 Irinotecan A A Bosutinib Nimotuzumab KX2-391 Docetaxel Neratinib I A Gefitinib I I Erlotinib Dasatinib (Sprycel) PF-00299804 I I I Cetuximab A Pertuzumab AZD-0530 Matuzumab Approved/Launched A BIBF-1120 Everolimus (RAD-001) I Cisplatin Brivanib XL-999 I Sirolimus (Rapamycin) AV-370 Figitumumab (CP-751871) Liposomal Cisplatin A Temsirolimus (CCI-779) Gemcitabine TKI-258 Carboplatin I F-50035 Enzostaurin XL-281 A Pemetrexed Ifosfamide Talactoferrin Registered Deforolimus (AP23573) Cixutumumab A Sapacitabine Lucanix AVE-1642 Imprime PGG AZD-6244 PX-866 NOV-002 AMG-479 Mage-A3 Vorinostat A PicoPt BHB022 Stimuvax MKC-1 OSI-027 Oblimersen XL-184 I Temozolomide Phase III Retaspimycin R-1507 A GI4000 BEZ-235 / BTGT226 / BKM CimaVax EGF Etinostat Panobinostat AT-101 OSI-906 Tremelimumab AZD-8055 Decitabine obatoclax PF-3512676 (agatolimod) IMO-2055 Pralatrexate ARRY-886 XL-228 ABT-263 belinostat Glufosfamide Phase II EC-145 AUY922 Vical-2 vaccine MDX-1105 SNX5542 V-935 GVAX MGCD-0103 VX-001 AS-1411 V-930 Naptumomab ABT-263 A Phase I Source: Compiled by Neeta Somaiah & George Simon.

  12. 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

  13. 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.

  14. 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.

  15. 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

  16. 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

  17. 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

  18. 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?

  19. 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

  20. Questions

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