SNI Clinical Trials Neuro-oncology SNI Clinical Trials Neuro-oncology Glioblastoma – Newly diagnosed • Immunotherapy - DCVax- tumor antigen pulsed dendritic cells - Celldex- EGFR VIII mutant vaccine • Small molecule VEGF inhibitor - cediranib • NovoCure TTF device High grade glioma – Recurrence • Retroviral gene therapy -cytosine deaminase prodrug conversion SNI Clinical Trials Neuro-oncology GBM Newly Diagnosed - Phase II ACT IV A Randomized, Double-Blind, Controlled Study of Rindopepimut/GM-CSF with Adjuvant Temozolomide in Patients with Newly Diagnosed, Surgically Resected, EGFRvIII-positive Glioblastoma The EGFR Mutation Variant III (EGFRvIII) EGF-binding domain Transmembrane domain Intracellular domain NH2 COOH wtEGFR EGFRvIII • Tumor-specific oncogene ideally suited for immune targeting • Expressed in 1/3 of primary glioblastoma, but not in normal tissue • In-frame deletion of exons 2-7 results in constitutively active protein with unique amino acid sequence at the fusion junction • Epitope is in the extracellular domain; accessible to antibodies and highly immunogenic Rindopepimut (CDX-110) Vaccine designed to generate a specific immune response against EGFRvIII-expressing tumors • “Off the shelf” vaccine recognized across HLA types • Consists of the EGFRvIII antigen (unique 13 amino acid peptide sequence) chemically conjugated to Keyhole Limpet Hemocyanin • Delivered as intradermal injection of 500ug rindopepimut with 150ug GM-CSF • Stable lyophilized formulation O N O S N KLH O LEEKKGNYVVTDHC >30 ACT IV Study Design R A N D O M I Z A T I O N Vaccine Priming Adjuvant Temozolomide and Vaccine Therapy (TMZ-V, 6-12 cycles) Vaccine Maintenance Therapy (VMT) § § D1 D15 • Dose vaccine days 1 and 15 of Vaccine Priming cycle • Start cycle within 4 days after randomization and within 7-14 days after completion of CRT C1D1 C1D22 C2D22 C3D22 etc…. • Vaccine or placebo is administered Day 22 of each TMZ cycle • Begin TMZ no sooner than 6 days after administration of the second vaccine priming dose • Begin TMZ no sooner than 28 days after completion of CRT • Begin TMZ when ANC 1000/L and platelets 100,000/L Follow Up C1D1 C2D1 etc… If no disease progression after TMZ, continue dosing vaccine every 28 days (Day 1 ±3 days of each 28 day cycle) until intolerance or disease progression Follow-up for overall survival every 12 weeks after disease progression • TMZ dosed days 1-5 of each 28 day cycle § CRT Temozolomide Dosing Vaccine or Placebo Dosing Tumor Assessments – every twelve weeks Chemoradiation Therapy Treatment will be discontinued upon disease progression, unacceptable treatment-related toxicity, or patient refusal to continue study treatment SNI Clinical Trials Neuro-oncology GBM Newly Diagnosed - Phase II DCVax-L An Autologous, Dendritic Cell Based Therapeutic Vaccine for Newly Diagnosed Glioblastoma Multiforme SNI Clinical Trials Neuro-oncology DCVax-L Vaccine produced from: - Autologous dendritic cells generated from PBMC - Pulsed with autologous GBM lysate - Subcutaneous vaccine injections - During adjuvant TMZ SNI Clinical Trials Neuro-oncology GBM Recurrence - Phase I Tocagen 511 A Phase 1 Ascending Dose Trial of the Safety and Tolerability of Toca 511, a Retroviral Replicating Vector, Administered to Subjects at the Time of Resection for Recurrent High Grade Glioma and Followed by Treatment with Toca FC, Extended-Release 5-FC Toca 511 delivers yeast cytosine deaminase gene into replicating tumor cells U3 R U5 gag pol env U3 R U5 IRES 5-FC • 5-FC is orally available • 5-FC crosses the BBB CD Cytosine Deaminase 5-FU Infected tumor cells convert 5-FC to 5-FU Toca 511 injected into tumor 5-FC taken orally Toca 511 5-FC 5-FU CD Tumor Normal tissue Toca 511 spreads through tumor Toca 511= virus + CD gene 2012 Copyright Tocagen Inc. Tumor regression SNI Clinical Trials 30 Translational Studies MS Clinical Studies 25 Brain Tumor N = 79 20 15 Pituitary Epilepsy 10 Spine Cerebrovascular 5 Neuro-ophth Movement Disorders Psychiatry Stroke 0 Research Patient Enrollment 800 700 600 500 400 300 Dec-10 Jan-11 Feb-11 Mar-11 Apr-11 May-11 Jun-11 Jul-11 Aug-11 Sep-11 Oct-11 Nov-11 Dec-11 Jan-12 SNI Clinical Trials Swedish Neuroscience Inst