Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Clinical Trials for Brain Tumor Patients

5,134 views

Published on

Audio and slides for this presentation are available on YouTube: http://youtu.be/6W_xoH4s-Yk

Dr. Patrick Wen, of Dana-Farber Cancer Institute's Center for Neuro-Oncology, discusses current clinical trial options for brain tumor patients and some of the new therapies available in neuro-oncology. This presentation was originally given at Dana-Farber Cancer Institute on Dec. 4, 2013.

  • Be the first to comment

Clinical Trials for Brain Tumor Patients

  1. 1. Clinical Trials In Neuro-Oncology Patrick Y. Wen, M.D. Center For Neuro-Oncology, Dana-Farber Cancer Institute Division of Cancer Neurology, Department of Neurology Brigham and Women’s Hospital Harvard Medical School
  2. 2. Clinical Trials • Phase I • Find the maximum safe dose • Phase II • Determine efficacy of drug at the maximum safe dose • Phase III • Compare effectiveness of drug to standard of care
  3. 3. Update on Novel Therapies • Targeted Molecular Therapies • Antiangiogenic Therapies • Stem Cell Therapies • Immunotherapies • Tumor Metabolism
  4. 4. Targeted Molecular Therapies
  5. 5. Wen & Kesari. N Engl J Med 2008;359:492-507
  6. 6. Frequent genetic alterations in three critical signalling pathways. The Cancer Genome Atlas Research Network Nature 000, 1-8 (2008) doi:10.1038/nature07385
  7. 7. PATIENTS WITH SAME DIAGNOSIS ARE NOT ALL THE SAME Predicted good response to drug or combination of drugs Predicted poor or no response to drug or combination of drugs Increased likelihood of toxicity of drug or combination of drugs CHANGE DRUGS CHANGE DRUGS
  8. 8. PATIENTS WITH SAME DIAGNOSIS ARE NOT ALL THE SAME Predicted good response to drug or combination of drugs Predicted poor or no response to drug or combination of drugs Increased likelihood of toxicity of drug or combination of drugs CHANGE DRUGS CHANGE DRUGS
  9. 9. PATIENTS WITH SAME DIAGNOSIS ARE NOT ALL THE SAME Predicted good response to drug or combination of drugs Predicted poor or no response to drug or combination of drugs Increased likelihood of toxicity of drug or combination of drugs CHANGE DRUGS CHANGE DRUGS
  10. 10. PATIENTS WITH SAME DIAGNOSIS ARE NOT ALL THE SAME Predicted good response to drug or combination of drugs Predicted poor or no response to drug or combination of drugs Increased likelihood of toxicity of drug or combination of drugs CHANGE DRUGS CHANGE DRUGS
  11. 11. Personalized Medicine The Right Drug for the Right Person at the Right Time This is the overarching goal of Dana-Farber’s research
  12. 12. Dramatic clinical responses to drugs targeting BRAF  only in patients with the BRAF mutation! Baseline Day 15 Flaherty et al., ASCO 2009 (abstract #9000)
  13. 13. Sequencing Epigenetic Analysis Set of activated kinases and pathways Combinations of appropriate drugs Ivy Foundation Early Phase Clinical Trials Consortium DF/HCC MSKCC UCLA UCSF MDACC U Utah
  14. 14. • Oncopanel 275 genes • Array CGH
  15. 15. DFCI/BWH “Living” Tissue Bank Program CNS Tumor Patient Primary tumor Gentle Dissociation Papain Tumorsphere culture - Hydrogel Comprehensive Analysis - EGF and FGF Laminin culture - Laminin coating - EGF and FGF IHC Stem/Lineage Assessment RNA Expression Affy U133 2.0 Plus Whole Genome Copy Number Agilent aCGH 1M Somatic Mutation Sequenom Xenograft - Orthotopic (striatum) - SCID mice - Serial passage Sphere culture for GBM – Howard A. Fine, Cancer Cell 06 Laminin - Peter Dirks, Cell Stem Cell 09 Slide courtesy of Keith Ligon MD
  16. 16. GBM Patient-derived Cell Lines Reproduce Key Features of GBM as in vivo preclinical models A Infiltrating borders BT112 Necrosis BT112 B Pushing borders BT189 Microvascular Proliferation BT187 C Gliomatosis BT179 Numa Intratumoral Hemorrhage BT189 Slide courtesy of Keith Ligon MD
  17. 17. Access Across Blood Brain Barrier is Important
  18. 18. BKM120 Crosses the BBB BKM120 557 BKM 4h BKM120 Heme
  19. 19. Convection-Enhanced Delivery
  20. 20. GRN1005
  21. 21. GRN1005 Low density lipoprotein receptor related protein (LRP1)
  22. 22. GRN1005
  23. 23. GRN1005
  24. 24. GRN1005
  25. 25. GRN1005
  26. 26. GRN1005
  27. 27. Wen & Kesari. N Engl J Med 2008;359:492-507
  28. 28. PI3 Kinase/Akt/MEK Inhibitors MEK inhibitor Growth Factors, etc AZD6244 GSK1120212 GDC0973 MSC1936369B MEK162 Ras Raf Mek Erk Proliferation PI3K inhibitor XL765 XL147 BKM120 PX866 GDC0084
  29. 29. 12-7-06 1-25-07 10-12-13
  30. 30. Mechanisms of Resistance (Bergers and Hanahan Nat Rev Cancer 2008)
  31. 31. Adaptive Evasion to VEGF inhibitors FGFs Angiopoietins Src, integrins, FAK, etc Ephrins Increased invasiveness Anti-VEGF therapy leads to tumor stasis or shrinkage, and blood vessel regression Upregulation of additional proangiogenic growth factors PIGF SDF-1 PDGF Increased pericyte coverage to protect blood vessels Recruitment of vascular progenitors and proangiogenic monocytes
  32. 32. Strategies To Overcome Resistance FGFR – BIBF1120 (VEGFR+FGFR+PDGFR) – E7080 (VEGR+FGFR+PDGFR) Angiopoietins – AMG 386 (angiopoietin 1/2 neutralizing peptibody) CXCR4 – Plerixafor (AMD3100) CD105 – TRC105
  33. 33. Neural Stem Cells
  34. 34. Single cell from neural tube “neurosphere” disaggregate & subcultivate plate onto adherent surface in factor-fee medium Neuron Astrocyte Oligodendrocyte
  35. 35. Glioma Stem Cells Wen PY, Kesari S. N Engl J Med 2008;359:492-507
  36. 36. Grow as neurospheres in vitro. Neurospheres are multipotent Highly tumorigenic in SCID mice. Negative control: (hemispherectomy tissue) Oligodendrocyte Astrocyte Neuron
  37. 37. GDC-0449 D. D. Von Hoff et al., N. Eng. J. Med. 164, 1164(2009). Science 23 October 2009: Vol. 326. no. 5952, pp. 572 - 574 DOI: 10.1126/science.1179386
  38. 38. Glioma Stem Cells Wen PY, Kesari S. N Engl J Med 2008;359:492-507
  39. 39. PTEN null lines: BKM120 and LDE225 Targeting tumor cells and stem cells Courtesy of Rosalind Segal, DFCI
  40. 40. Immunotherapy
  41. 41. Immunotherapies Vaccines • Dendritic cell • DCVax • ICT107 • Peptides • Stemline • CDX110 (Rindopepimut) Ipilimumab PD1 and PDL1 antibodies
  42. 42. Targeting Tumor Metabolism The Warburg Effect Otto Heinrich Warburg, 1883–1970 Vander Heiden et al, 2009.
  43. 43. Vander Heiden et al, 2009. Teicher et al. Clin Cancer Res 2012;18:5537-5545
  44. 44. IDH1 and IDH2 Mutations in Human Gliomas Yan H et al. N Engl J Med 2009;360:765-773
  45. 45. Survival of Adult Patients with Malignant Gliomas with or without IDH Gene Mutations Median Survival 31 mo vs 15 mo Median Survival 65 mo vs 25 mo Yan H et al. N Engl J Med 2009;360:765-773
  46. 46. IDH 1 & 2 as a Therapeutic Targets Reitman et al, 2010.
  47. 47. Science 2013
  48. 48. Andronesi et al Sci Transl Med. 2012
  49. 49. Stem Cell Therapy
  50. 50. GBM Trials Newly-diagnosed GBM With RT • • • • • • BKM120 (PI3K inhibitor) MK1775 (WeeI Inhibitor) ABT414 DCVax Rindopepimut (CDX110) PLX3397 (CSF-1R) Adjuvant • BKM120 (PI3K) • MK1775 (Wee1 Inhibitor) • ABT 414
  51. 51. Recurrent GBM Trials Anti-VEGF/VEGFR •Avastin + Plerixafor + Avastin •Avastin + AMG386 •Avastin + TRC105 •Avastin + MLN0128 •VB-111 (viral vector targeting angiogenesis) Targeted Therapies • BKM120 (PI3K) • BKM120 + LDE225 (Smo) • BKM120 +INC280 • GDC0084 (PI3K) • PF-00299804 (pan EGFR) • ABT414 +TMZ (EGFR antibody) • LY835219 (CDK4/6) • BGJ398 (FGFR) • Fliclatuzumab (HGF) • AG120 (IDH-1 inhibitor) Immunotherapy •Avastin + CDX110 vaccine • Ipilimumab/Nivolumab/Avastin • Avastin + HSPPC96
  52. 52. Other Brain Tumor Trials Therapeutic Trials Low-Grade Glioma • RT vs TMZ (ECOG/RTOG/NCCTG) •AG120 (IDH1 inhibitor) Meningioma • Avastin Brain Metastases • GRN1005 Ependymona • TMZ+lapatinib NF2 Schwannomas • PTC299 Plexiform neurofibroma • Rapamycin Fatigue • Armodafinil (Nuvigil) + RT Primary CNS lymphoma • Premetrexed • Allo-BMT Non-Therapeutic Trials • Vimpat seizure prophylaxis • FLT-PET, FET-PET • FMiso-PET
  53. 53. Thank You!

×