Off-Label Treatments. Clinical Trials for Recurrent GBM UCSF Radiation Oncology Course: Management of Recurrent Disease. Outline

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1 Off-Label Treatments Clinical Trials for Recurrent GBM UCSF Radiation Oncology Course: Management of Recurrent Disease Jennifer Clarke, MD, MPH Assistant Professor Division of Neuro-Oncology Depts of Neurological Surgery and Neurology Brain Tumor Research Center, UCSF Almost everything I will discuss today involves off-label treatment Outline Nuts and Bolts of Clinical Trials Growth Factor Pathways Ongoing Trials Nuts and Bolts of Clinical Trials Phase I: toxicity/safety Phase II: efficacy Phase III: novel versus standard of care Phase I and Phase II >> Phase III Nuts and Bolts of Clinical Trials Treatments Novel Targeted Agents: Small-molecule inhibitors ( -ib) Antibodies ( -ab) Combinations of Cytotoxic and Targeted Agents Immunotherapy Surgically-based trials: new Rx delivery methods Re-irradiation trials Patient Populations: Recurrent GBM first 1

2 GBM: multiple genetic types P53 mutation (>65%) EGFR: PDGF-A, PDGFR amplification (~40%) overexpression(~60%) overexpression (~60%) Low grade astrocytoma LOH 19q (~50%) RB alteration (~25%) Anaplastic astrocytoma MDM2: amplification(<10%) overexpression(~50%) p16 deletion (30-40%) Complexity of Targeting Signaling Pathways in GBM: The MAPK and PI3K/AKT pathways. Sorafenib Erlotinib/lapatinib/XL184 Rapamycin CCI-779 RAD 001 LOH 10q PTEN mutation (5%) PDGFR amplification (<10%) Secondary glioblastoma LOH 10p and 10q PTEN mutation (~30%) RB alteration Primary glioblastoma (de novo) Sorafenib PTK 787 SU 5416 Bevacizumab Figure from Sekulic A, Haluska Jr P, Miller AJ, et al. Malignant melanoma in the 21st Century: the emerging molecular landscape. Mayo Clin Proc. 2008;83(7): Used with permission Mayo Foundation for Medical Education and Research Targeted Agents: HGF and VEGF pathways XL184: small molecule inhibitor targets: VEGFR c-met Targeted Agents: Hedgehog pathway PTCH encodes Patched, receptor for Hedgehog (Hh) protein family; normally, Patched inhibits Smo Smo activates Gli transcription factors Hh pathway active in gliomas, particularly in CD133+ cancer stem cells GDC-0449 is Smo inhibitor Figure from Sekulic A, Haluska Jr P, Miller AJ, et al. Malignant melanoma in the 21st Century: the emerging molecular landscape. Mayo Clin Proc. 2008;83(7): Used with permission. 2

3 Immunotherapy Both active (vaccine) and passive (antibodies) strategies being researched Vaccine strategies: Target tumor-specific antigen (e.g. EGFRvIII) Create autologous vaccine Dendritic cell strategy Heat-shock protein (HSP) strategy Focus shifting to up-front treatment Immunotherapy: HSP Vaccine HSPs Bind Peptides: Normal, Mutated and Cancer Peptides HSPs function as peptide chaperones in every nucleated cell Antigenic Peptides Normal, mutated and cancer peptides HSP Mechanism of Action Injection of HSP-peptide complexes? CD36 CD91 CD40 CD14 TL-R2 TL-R4 Internalization and re-presentation of peptides APC CD91 MHC class I/peptide Nucleus Induction of cytokines and chemokines Crosspresentation Srivastava P. Nature Rev 2002;2: CD8 + T cell TCR MCP-1 MIP-1α RANTES NO CD4 + T cell MHC class II/peptide IL-12 TNF-α IL-1β GM-CSF NK cells Immunotherapy: HSP Vaccine Tumor must be operable, with near-gtr of enhancing tissue Tissue taken directly from OR for processing Vaccine made from peptide-bearing HSPs, thought to be specific to individual tumor If MRI 4 wks post-op relatively stable, vaccine treatment initiated 3

4 Novel Drug Delivery Methods: Convection-Enhanced Delivery (CED) Into the tumor Around the tumor Tumor with infiltrative cells Volume of drug delivered Novel Delivery Methods: CED Studies Agents tested include: Chemotherapy (paclitaxel) Conjugated toxins (IL13-pseudomonas exotoxin, transferrin/diptheria toxin, TGF alfa pseudomonas exotoxin) Antisense oligonucleotides- (TGF-beta2 mrna) Radioactive monoclonal antibodies Planned studies: Viruses Nanoliposomal agents Improved Targeting Many GBMs recur locally, within initial radiation field Re-irradiation with SRS techniques can be an effective strategy However, most (83%) 1 re-recur locally again One explanation: inadequate identification/ targeting of viable tumor UCSF retrospective data: MRS Improved Targeting Strategy: combination of MRS and gadolinium images to select target Phase II study, recently opened at UCSF 1 McDermott MW, et al. Radiosurgery, ed. Kondziolka D, 1996, v1,

5 Radiosensitization Tumor response to radiation injury involves VEGF pathway GBM itself has high levels of VEGF activation Preclinical studies have shown synergy between anti-angiogenic agents and XRT Gutin, et al. study showed promising results with bevacizumab and SRS Radiosensitization 25 patients enrolled recurrent HGG (20 GBM and 5 grade 3) 3.5 cm enhancement in longest diameter Bevacizumab 10 mg/kg q 14 days If MRI stable after 1 st cycle, received hypo-frxnated SRS to 30 Gy (6 Gy x 5) Bevacizumab continued until progression Gutin, et al. Int J Rad Onc Biol Phys, 2009, 75(1): Radiosensitization 24 of 25 pts received SRS 13 pts (52%) had objective response PFS-6 for GBM pts was 65% Median OS for GBM was 12.5 mo In general, well-tolerated: 1 CNS + 1 GI hemorrhage, no symptomatic necrosis Gutin, et al. Int J Rad Onc Biol Phys, 2009, 75(1): Baseline Post-treatment Summary Recurrent GBM remains a very difficult tumor to treat Research ongoing across multiple areas: targeted agents, immunotherapy, novel delivery methods, viral therapy, reirradiation techniques, etc. Progress being made TMZ, bevacizumab, etc. there is hope! 5

6 Thank You! Notch pathway is active in neural development Pathway is overactive in at least a subset of GBMs May tie into Ras pathway Targeted Agents: Notch pathway Figure from Sekulic A, Haluska Jr P, Miller AJ, et al. Malignant melanoma in the 21st Century: the emerging molecular landscape. Mayo Clin Proc. 2008;83(7): Used with permission. 6