Molecular Epidemiology. Financial Disclosures. Central Nervous System Tumors Neuro-Oncology Clinical Research

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1 Financial Disclosures Update on clinical trials for malignant glioma Susan M. Chang MD, Director of Division of Neuro-Oncology Brain Tumor Research Center Department of Neurological Surgery UCSF Research support: Schering Neopharm Consulting agreement: Genentech Celldex August 2007 Central Nervous System Tumors Neuro-Oncology Clinical Research Heterogeneous group of primary tumors Approx 17,500 cases diagnosed/year Majority are glial- astrocytic, oligodendroglial, ependymal Malignant glioma, grade III and IV, are most common Median survival for GBM is months with multimodality therapy Great need for novel therapeutic strategies Non-Therapeutic Trials Neuro-Epidemiology Neuro-Imaging Patient Outcomes Therapeutic Trials Phase I/II/III trials Molecular Epidemiology Markers of Exposure Cancer and Precancer Markers PET Neuro-imaging research: Physiologic/functional imaging DWI pmri 1 H MRS Exposure Internal Dose Bio Effective Dose Early Bio Effect Altered Struc/ Func Clinical Cancer Progression Exposure assessments Questionnaires Environmental measurements Genetics-Genomics Biomarkers Transcriptomics Proteomics Metabolomics Markers of susceptibility/resistance Intervention opportunities After:Molecular Epidemiology, Schulte & Perera Anatomic Imaging 1

2 MR Spectroscopy Patient Outcomes Research Tumor Tumor burden burden by MRI+MRSI by MRS predicts tumor relapse prior to MRI Cancer Care and Survivorship Quality of Life Symptom Clusters Cognitive Function Caregiver Research Education MRI predicts progression, MRSI predicts primarily necrosis Neuro-Oncology Therapeutic Clinical Trials Surgery for Glioma Efficient and accurate evaluation of novel therapies Determine true benefit of therapy while maximizing resources- patients, time, financial, personnel effort Phase I- toxicity studies Phase II- preliminary efficacy studies Phase III- improvement in patient outcomes over standard therapy Maximal, safe resection to achieve the following goals 1) Relieve mass effect and improve symptoms 2) Provide tissue for histological diagnosis, molecular and cytogenetic analysis 3) Improve survival Techniques for maximal, safe resection Subcortical White Matter Tracts using DTI SHOULDER WRIST TUMOR Most reports of techniques have been retrospective reviews of single institution experience Pre-operative functional mapping using diffusion tensor imaging Intra-operative motor and speech mapping Intra-operative imaging Anomia Motor mouth Anomia Speech arrest 2

3 Surgery for Glioma Surgery for malignant glioma Surgery to extend survival ( cytoreduction ) the most controversial of the three goals No randomized trials completed or planned -- size of such a trial would be substantial Nonrandomized trials all suffer from selection bias tendency for favorable patients to undergo resection Definition of surgical margins and assessment of extent of resection?? Stummer et al (Lancet Oncol:5/06) Phase III study of fluorescence guided surgery with 5- aminolevulinic acid (5-ALA) for resection of malignant glioma 322 pts who were selected for GTR were randomized GTR achieved in 65 % pts who received 5-ALA vs 36 % who did not 6 month PFS was 41% vs 21% Post-op neurologic complications similar Effect on survival was not a primary outcome Surgeons were not blinded to treatment group Clinical Trials- Radiation Clinical Trials- Radiation Standard radiation therapy for GBM- 60 Gy administered in 2Gy fractions over 30 treatments to tumor and 2 cm margin Strategies to increase dose to tumor while sparing normal tissue Previous studies of focal radiation with radiosurgery or brachytherapy did not show a survival advantage in GBM Accelerated radiotherapy has not resulted in improved survival Role of intensity modulated radiotherapy being evaluated Radiosensitizers have not afforded a survival benefit? Role of targeting treatment using physiologic imaging? Approaches to reduce radiation injury- hyperbaric oxygen Clinical Trials- Cytotoxic agents Anaplastic oligo / OA Meta-analysis of nitrosourea in malignant glioma trials suggest modest improvement of survival In late 1980s, chemosensitivity of anaplastic oligo / oligoastro was one of the most exciting developments in neuro-oncology High correlation between 1p/19q loss (both alleles) and radiosensitivity, chemosensitivity Two important RCTs published in June 2006 (JCO) compared XRT plus PCV chemo to XRT alone (either neoadjuvant or adjuvant) Both trials found modest difference in progressionfree survival, with no difference in overall survival CTX failed to provide benefit regardless of 1p/19q status 3

4 Anaplastic O/OA: RTOG 9402 Anaplastic O/OA: RTOG 9402 Anaplastic O/OA: RTOG 9402 Anaplastic oligo/oa Mechanism of loss of both chromosomal moieties now known to be due to formation of a derivative chromosome through translocation of long arm of 1 plus short arm of 19 Reason this affects clinical course still unknown Jenkins RB Cancer Res (Oct 2006) Griffin CA et al, J Npath Exp Neurol Oct 2006 Anaplastic oligo/oa Based on the results of these studies, future clinical trials of grade III tumors will stratify treatment based on 1p 19q deletion status Redefines eligibility of patients based on molecular profiling rather than standard histology Highlights the importance of tissue acquisition to assess patients for clinical trials NH 2 C O Temozolomide: Novel Imidazotetrazine Temozolomide Spontaneously Converts to MTIC at Physiologic ph N N N N N CH 3 O Temozolomide ph >7.0 Spontaneous hydrolysis NH 2 C O N N MTIC N N N H NH 2 C + NH + N N CH 2 3 CH N 3 N O AIC Methyldiazonium ion Denny BJ et al. Biochemistry 1994;33:9045 4

5 Pre-Treatment MRI : recurrent AA Response following 2 five-day cycles Q month of temozolomide % Survival advantage for temozolomide Recent EORTC randomized trial in newly diagnosed GBM showed a survival advantage to the use of radiation with concurrent and adjuvant temozolomide (an oral alkylating agent) as compared to radiation alone (Stupp et al, NEJM 2005) TMZ/RT months RT RT TMZ/RT Median OS, mo: yr survival: 10% 26% HR: 0.63 [0.52,0.75] p < Clinical Trials- Cytotoxic agents Clinical Trials- Targeted agents Findings of genetic marker (06methyl guanine-dna methyltransferase (MGMT) that affects temozolomide sensitivity Optimal scheduling of standard chemotherapy such as temozolomide being evaluated Strategies to reverse drug resistance being pursued Ongoing RTOG 0525 study Newly diagnosed GBM randomized to XRT/temo and either standard adjuvant versus dose dense temozolomide MGMT status evaluated in all patients Knowledge of dysregulated signaling pathways in glioma allow for selection of targeted therapies Signal transduction agents are drugs that target a specific signal/switch pertaining to Tumor cell proliferation Tumor cell survival/apoptosis Angiogenesis Invasion/migration May target surface receptors, tumor microenvironment or tumor vasculature Monoclonal Antibody Receptor Signaling Pathways and Therapeutics Ligand binding inhibited by monoclonal antibody Targeting abnormal signaling pathways Combinatorial Strategies EGF TGF-α ZD1839/OSI 774/GW572016/AEE 788/PKI166 C225 R R K K EGF-R extracellular compartment cytoplasmic membrane cytosol Target cell Nucleus Signal transduction Enzyme activation Gene Transcription Enzyme inhibitors act here Signaling inhibitors may act here (antisense strategies, gene therapy) PTEN Rapamycin CCI-779 RAD 001 Bay PTK 787 SU 5416 Avastin HIF 1 VEGF PIP 2 mtor PIP 3 PI3K PDK Akt FKHR, GSK-3, Bad Ras GTP PLC PKC R Raf MEK1,2 MAPK/ Erk1,2 Bay Proliferation Apoptosis Angiogenesis Metastasis Angiogenesis Proteinsynthesis Cell cycle regulation Cell survival Transcription Proliferation 5

6 Challenges in the evaluation of targeted agents Determination of optimal biological dose rather than maximal tolerated dose Selection of target to be modulated and appropriate agent Assessment of activity- modulation of target and clinical benefit Standard assessment of tumor response inadequate- e.g. anti- VEGF agents target the abnormal tumor vasculature and can normalize the BBB thereby resulting in an immediate and dramatic decrease in enhancement which is not a measure of antitumor effect Multimodality Therapy Advantage of different mechansims of antitumor effect May have non-overlapping toxicities- safe administration of combinatorial treatments Synergistic effect with cytotoxic agents/radiation being explored e.g. Bevacizumab/CPT11- results of a phase II study showed RR of 60% and 6 mo PFS of 39% Limitations of therapy for malignant glioma Surgery Due to the infiltrating nature, complete resection is difficult Radiation Dose is limited by secondary brain injury Chemotherapy Inadequate delivery of drug to tumor Drug resistance Systemic side effects Strategies to improve delivery of drugs into the brain A. B. C. D. Disease Challenge: Infiltrating Tumor Component Interstitial therapy Delivery of targeted therapy into the brain remains one of the largest obstacles in brain tumor therapy Direct intracavitary or interstitial therapy continues to be investigated Chemotherapy impregnated biodegradable wafers (carmustine, 5FU) Radiation (I131 labeled antitenascin monoclonal antibody, gliasite delivery) Novel agents (TNF-alpha, liquid crystalline chemotherapy, I-131 TM-601 or scorpion venom) 6

7 Convection-Enhanced Delivery (CED) CED studies Catheter Surgical resection cavity Drug Concentration Drug delivered by CED Drug delivered by diffusion Drug Distance from source Agents tested include: Chemotherapy (paclitaxel) Conjugated toxins (IL13-pseudomonas exotoxin, transferrin/diptheria toxin, TGF alfa psuedomonas exotoxin) Antisense oligonucleotides- (TGF-beta2 mrna) Radioactive monoclonal antibodies Planned studies: Viruses nanoliposomal agents Intraparenchymal Drug Delivery CED studies Challenges include optimal catheter placement and delivery and assessment of volume of distribution of agent These surgically based studies highlight the importance of the involvement of the neurosurgeon in the design, development, conduct and evaluation of these trials Other experimental treatment approaches Gene therapy approaches Using viruses that can and cannot replicate Use of neural stem cells Delivery of therapeutic agents Conversion of prodrugs Immunotherapy trials Nonspecific activation of the immune system Activation of cellular immune response Using antibodies directed at specific tumor antigens (autologous tumor dendritic cell vaccine, heat shock protein vaccine ) UCSF Neuro-Oncology Clinical Trials Newly diagnosed disease Phase II Temozolomide for Low Grade Glioma Enzastaurin for GBM Eli Lilly Phase I/II RTOG 0525 for GBM- standard adjuvant temodar vs dose intense temodar UCSF Neuro-Oncology Clinical Trials Recurrent Malignant Glioma Phase II Heat Shock Protein Vaccine NABTC studies for recurrent disease NABTC (Cilengitide) NABTC (Depsipeptide) NABTC (GW) NABTC (OSI/CCI) NABTC (SAHA/Tmz) NABTC (Bay+ OSI/CCI/R11)) NABTC (VEGF-trap) 7

8 Neuro-Oncology Clinical Research Neuro-Oncology Clinical Research Continued need for the advancement in understanding of the scientific basis of glioma formation Insight into molecular biology and cytogenetics important for translation to the clinic Evaluation of novel therapies required Quality of Life studies important in conjunction with therapeutic trials Cooperative and multidisciplinary effort essential Role of the neurosurgeon is critical to the success of clinical research in Neuro-Oncology: Development of standard operating procedures for intraoperative high quality tissue acquisition for molecular and cytogenetic characterization (NIH- cancer genome atlas initiative and the glioma molecular diagnostic initiative) Tissue is important for assessment of biomarkers for diagnosis, prediction of response, prognosis, selection of patients for clinical trials Real-time Neuro RSP: Radiology, Surgery, Pathology Tissue arrays Distinctive Molecular Profiles of High-Grade and Low-Grade Gliomas based on Oligonucleotide Microarray Analysis. Rickman et al Cancer Research 2001 Neuro-Oncology Clinical Research Role of the neurosurgeon is critical to the success of clinical research in Neuro-Oncology: Identification of important surgically based questions for malignant glioma with plan for prospective evaluation Standardization of surgical procedures for relevant clinical trials e.g. CED Translational effort of many neurosurgeon clinician/scientists to design, develop, conduct and evaluate prospective therapeutic surgically based clinical trials 8