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January 2011 0825-1 RTOG Protocol No: 0825 Protocol Status: Opened: April 15, 2009 Title: Phase III Double-Blind Placebo-Controlled Trial of Conventional Concurrent Chemoradiation and Adjuvant Temozolomide Plus Bevacizumab Versus Conventional Concurrent Chemoradiation and Adjuvant Temozolomide in Patients With Newly Diagnosed Glioblastoma. Patient Population: Objectives: Patients must have histopathologically proven diagnosis of glioblastoma or gliosarcoma (WHO grade IV) confirmed by central review prior to step 2 registration. Tumor tissue must be determined by central pathology review prior to step 2 registration to be of sufficient size for analysis of MGMT status and determination of molecular profile. The tumor must have a supratentorial component. Primary: To determine whether the addition of bevacizumab to temozolomide and radiation improves efficacy as measured by progression-free and/or overall survival. Secondary: To determine whether the tumor molecular profile conferring a mesenchymal/angiogenic phenotype is associated with a selective increase in benefit, as measured by either overall survival or progression-free survival, from the addition of bevacizumab. To compare and record the toxicities of the conventional and bevacizumab-containing regimens. Tertiary: To determine the differential acute effects associated with the addition of bevacizumab to temozolomide and radiation, as compared to the conventional arm, on measures of neurocognitive function, health-related quality of life, and symptoms during radiation and across the longitudinal progression-free interval. To determine the relationship of neurocognitive function, health-related quality of life, and symptoms, with progression-free and overall survival. To determine the association between tumor molecular profile (i.e., mesenchymal/angiogenic phenotype and proneural phenotype) and neurocognitive function, health-related quality of life, and symptoms. To describe the association between health-related quality of life as measured by the EORTC-QL30/BCM20 and mean symptom severity as measured by the MDASI-BT in patients enrolled in this study. To evaluate the relationship between self-reported neurocognitive function and objectively measured tests of NCF. ACRIN 6686 Imaging Objectives Primary imaging objectives To assess the association between overall survival and K trans change from T1 to T2. To assess the association between overall survival and spin echo CBV change from T1 to T2. Secondary imaging objectives To assess the association between progression-free survival and K trans change from T1 to T2. To assess the association between progression-free survival and spin echo CBV change from T1 to T2. To assess the association between values of K trans and spin echo CBV measured separately at T0 and at T1, and overall and progression-free survival. To assess the association between overall survival and K trans changes from T0 to T1 and from T2 to T3. To assess the association between overall survival and spin echo CBV changes from T0 to T1 and from T2 to T3. To assess the association between overall survival and apparent diffusion coefficient (ADC) change from T0 to T1. To assess the association between overall survival and ADC change from T1 to T2. To assess the association between progression-free survival and ADC change from T0 to T1. To assess the association between progression-free survival and ADC change from T1 to T2. To assess the association between T1 values of ADC and overall and progression-free survival. To assess the association between change in lesion size between T1 and T3, as measured by advanced MRI, and overall and progression-free survival.

January 2011 0825-2 Aims for biomarker, imaging, quality of life study funding program supplement To assess the association between measures of change in enhancing tumor size at week 22 and overall survival in participants with glioma receiving chemoradiotherapy with and without bevacizumab. To assess the association between measures of change in T2-based tumor size at week 22 and overall survival in participants with glioma receiving chemoradiotherapy with and without bevacizumab. To assess the association between changes in ADC values and overall survival in participants with glioma receiving chemoradiotherapy with and without bevacizumab. Schema: STEP 1 REGISTRATION Central Pathology Tissue Screening Histology confirmation Confirmation of adequacy of tissue for MGMT analysis and molecular profile NOTE: Tumor tissue must be received and central review confirmation completed before STEP 2 registration can occur. STEP 2 REGISTRATION (Initial 3 weeks of chemoradiation treatment) Radiation (30 Gy in 2 Gy fractions) Concurrent daily temozolomide (qd X 21 d)* Analysis for MGMT methylation and molecular profile STEP 3 REGISTRATION RANDOMIZATION STEP: Must Occur by Day 10 After the Start of Radiation Arm 1 (Final 3 weeks of chemoradiation) Radiation (30 Gy in 2 Gy fx)* + daily TMZ (qd x 21 d) + placebo q 2 wks (continues without stop) 4 weeks after completion of chemoradiation: Temozolomide d 1-5 of 28-d cycle + placebo q 2 wks ; 12 cycle maximum** * Institution must be pre-credentialed. See protocol Section 5.0. ** Bevacizumab at progression at physician discretion. STRATIFY MGMT Methylation Status: Methylated vs. Unmethylated vs. Invalid Molecular Profile: Favorable vs. Unfavorable vs. Undetermined See protocol Section 6.0 for complete radiation therapy details. See protocol Section 7.0 for complete drug therapy details. Arm 2 (Final 3 weeks of chemoradiation) Radiation (30 Gy in 2 Gy fx)* + Daily TMZ (qd x 21 d) + bevacizumab q 2 wks (continues without stop) 4 weeks after completion of chemoradiation: Temozolomide d 1-5 of 28-d cycle + bevacizumab q 2 wks; 12 cycle maximum**

January 2011 0825-3 Study Chairs: Medical Oncology Patients entered through 11/01/2010: Mark R. Gilbert, M.D. RTOG Study 650 Deborah T. Blumenthal, M.D. RTOG RTOG 598 Kurt A. Jaeckle, M.D. NCCTG CTSU 32 David Schiff, M.D. ECOG CALGB 7 ECOG 4 Radiation Oncology NCCTG 4 Minesh Mehta, M.D. RTOG SWOG 3 Paul Brown, M.D. NCCTG ACOSOG 2 Neurosurgery Michael A. Vogelbaum, M.D., Ph.D. RTOG Neuropathology and Correlative Biology Ken Aldape, M.D. RTOG Howard Colman, M.D., Ph.D. RTOG Arnab Chakravarti, M.D. RTOG Medical Physics Robert Jeraj, Ph.D. Quality of Life Terri S. Armstrong, Ph.D., ANP-BC Neurocognitive Function Jeffrey S. Wefel, Ph.D. RTOG RTOG RTOG Imaging A. Gregory Sorensen, MD ACRIN Statisticians: Meihua Wang, Ph.D. Minhee Won, M.A. Research Associates: Barbara Kaiser, R.N., C.C.R.P. Sandrine Geinoz, Ph.D., C.C.R.P. Dosimetrist: Protocol Associate: Denise Manfredi, R.T.(T.) Kathryn Okrent, M.A. I. Summary: This study opened to accrual on April 15, 2009 with an original target sample size of 720. Based upon the analysis of the first 360 patients entered, the rate of patients not being randomized due to ineligibility, insufficient tissue, progression, patient refusal, or other reasons was very much underestimated (35% vs. originally projected 15%). Therefore the target sample size was increased to 940 in order to ensure there will be required 612 randomized patients. Six hundred fifty patients have been accrued to the first-step registration through November 1, 2010. Among these patients, 29 (4.5%) were still in the central pathology tissue screening process, 182 (28.0%) did not go to step 2 registration, and 439 (67.5%) passed the screening stage and continued to step 2 registration. Among the 439 patients registered to step 2, 23 (5.2%) were undergoing eligibility verification; on-study information was available for 379 (86.3%) patients, and concurrent RT+TMZ adverse event (AE) information was available for 289 (65.8%) patients. Tables 2.3-2.4 present patient case status in step 1 and 2 registrations, reasons for not going to step 2 registration, and pending eligibility. Following step 2 registration, patients could be potentially randomized to either Arm 1 or Arm 2 based on MGMT methylation status and molecular profile. Among the 439 patients registered to step 2, 416 (94.8%) were randomized, 10

January 2011 0825-4 (2.3%) were still in the randomization process and 13 (3.0%) were not randomized (Table 2.5). Table 2.6 provides patient case status for randomization and treatment assignment for randomized patients. Of 416 patients randomized, there were 365 (87.7%) with on-study information, 270 (64.9%) with concurrent RT+TMZ+BEV/placebo AE information, and 219 (52.6%) with AE information for the adjuvant stage. Table 3.1 lists the distributions of pretreatment characteristics for patients registered to step 2 and for the randomized patients registered to step 3. The distributions of stratification factors appear balanced between these two randomized arms. Adverse events are scored by CTCAE version 3.0. AE information is presented separately across the treatment arms for the concurrent RT+TMZ stage, the concurrent RT+TMZ+BEV/placebo stage, and the adjuvant stage. Table 4.1 lists the summary of worst AE per patient for these three stages. Tables 4.2 and 4.3 present the AEs for the concurrent RT+TMZ stage with respect to AEs reported as definitely, probably, or possibly related to protocol treatment (Table 4.2) and regardless of relationship to protocol treatment (Table 4.3). Tables 4.4 and 4.5 present the AEs for the concurrent RT+TMZ+BEV/placebo stage with respect to AEs reported as definitely, probably, or possibly related to protocol treatment (Table 4.4) and regardless of relationship to protocol treatment (Table 4.5). Table 4.6 and 4.7 present the AEs for the adjuvant stage with respect to AEs reported as definitely, probably, or possibly related to protocol treatment (Table 4.6) and regardless of relationship to protocol treatment (Table 4.7), respectively. Table 4.8 lists all grade 5 adverse events during and after protocol treatment. At this time, 343 (78.1%) radiotherapy reviews have been completed, and chemotherapy reviews have not yet been initiated. II. Administrative Information: Table 2.1 Patient Accrual Study sample size 942 Total patients entered through November 1, 2010 650 Average monthly accrual for the study 35.0 Average monthly accrual for the last 6 months 46.0 Projected completion date based on last 6 months May 2011

January 2011 0825-5 Table 2.2 Institutional Accrual RTOG Full Members and Affiliates (n=485) THOMAS JEFFERSON UNIV. HOSP. 110 THOMAS JEFFERSON UNIV. HOSP. 21 USON- NEW YORK ONCOLOGY 9 HEMATOLOGY, P.C. USON-WILLIAMETTE VALLEY CANCER 9 CENTER RADIATION ONCOLOGY ASSOCIATES 6 ROBERT WOOD JOHNSON UNIV. HOSP. 6 ST. LUKES HOSP. 6 SAINT BARNABAS MEDICAL CTR 5 TEL-AVIV MEDICAL CTR 5 PARKVIEW CANCER CTR/PARKVIEW 4 HOSP. USON- TEXAS ONCOLOGY-TYLER 4 ABINGTON MEMORIAL HOSP. 3 UNIV. OF CINCINNATI 3 UNIV. POINTE-PRECISION RADIOTHERAPY 3 USON-ARIZONA RADIATION ONCOLOGY 3 USON-FORT WORTH 3 AKRON GENERAL MEDICAL CTR 2 AULTMAN HOSP. 2 PENN STATE UNIV. AND THE MILTON S. 2 HERSHEY MEDICAL CTR ST. AGNES HEALTHCARE 2 USON- CANCER CTRS NORTHWEST- 2 SPOKANE USON- TEXAS ONCOLOGY LONGVIEW 2 CANCER CTR USON-CENTRAL INDIANA CANCER CTRS- 2 SOUTH ARIA HEALTH 1 HUDSON VALLEY ONCOLOGY ASSOC 1 UNIV. OF IOWA HOSP.S AND CLINICS 1 USON- TEXAS ONCOLOGY- SUGAR LAND 1 USON- TEXAS ONCOLOGY-PA BEDFORD 1 USON-TEXAS ONCOLOGY- SHERMAN 1 ARIZONA ONCOLOGY SERVICES FOUNDATION 29 UNIV. OF CALIFORNIA SAN FRANCISCO 28 KAISER PERMANENTE ROHNERT PARK 3 CANCER CTR KAISER PERMANENTE SANTA CLARA 3 MEDICAL CTR NEW MEXICO ONCOLOGY HEMATOLOGY 3 CONSULTANTS YALE CANCER CTR 3 ALTA BATES HOSP. COMPREHENSIVE 2 CANCER CTR KAISER PERMANENT RADIATION 2 ONCOLOGY CTR RANCHO CORDOVA KAISER PERMANENTE OAKLAND 2 KAISER PERMANENTE RADIATION 2 ONCOLOGY CTR ROSEVILLE POMONA VALLEY HOSP. MEDICAL CTR 2 RADIATION ONCOLOGY CTR OF WALNUT 2 CREEK - JOHN MUIR MED CT CITY OF HOPE MEDICAL CTR 1 JOHN MUIR MEDICAL CTR - CONCORD 1 CAMPUS KAISER PERMANENTE SOUTH 1 SACRAMENTO CANCER CTR WILLIAM W. BACKUS HOSP. 1 UNIV. OF TEXAS-MD ANDERSON CANCER CTR 27 UNIV. OF TEXAS-MD ANDERSON CANCER CTR 10 MAINE MEDICAL CTR 4 UNIV OF KANSAS COMPREHENSIVE CANCER 4 CTR MD ANDERSON CANCER CTR - 3 ORLANDO SAINT ELIZABETH REGIONAL MEDICAL 2 CTR THE MEDICAL CTR, INC., JOHN B. AMOS 2 CANCER CTR THOMPSON CANCER SURVIVAL CTR 2

January 2011 0825-6 INTERMOUNTAIN MEDICAL CTR 25 INTERMOUNTAIN MEDICAL CTR 7 DIXIE MEDICAL CANCER CTR 5 PENROSE CANCER CTR, PENROSE-ST. 5 FRANCIS HEALTH SERVICES UTAH VALLEY REGIONAL MEDICAL CTR 4 MCKAY-DEE HOSP. 2 LDS HOSP. 1 ST. JOSEPH HOSP. COMMUNITY CANCER 1 CTR SENTARA NORFOLK GENERAL HOSP. 1 WAUKESHA MEMORIAL HOSP. 2 GUNDERSON CLINIC 1 UNIV. OF TEXAS SOUTHWESTERN MEDICAL 19 SCHOOL OHIO STATE UNIV. MEDICAL CTR 11 UNIV. OF TEXAS SOUTHWESTERN MEDICAL 8 SCHOOL UNIV. OF WISCONSIN HOSP. 19 UNIV. OF WISCONSIN HOSP. 10 WAUSAU HOSP. CTR 7 RAPID CITY REGIONAL HOSP. 2 UNIV. OF ROCHESTER 18 UNIV. OF OKLAHOMA HEALTH SCIENCES CTR 4 MAIMONIDES MEDICAL CTR 3 UCSD UNIV. OF CALIFORNIA, SAN DIEGO 3 UNIV. OF NEW MEXICO-CANCER RESEARCH 3 AND TREATMENT CTR UNIV. OF ROCHESTER 2 BLOOMINGTON HOSP. 1 HIGHLAND HOSP. 1 SANDS CANCER CTR 1 UPMC-SHADYSIDE HOSP. 18 UPMC-SHADYSIDE HOSP. 4 UPMC CANCER CTR-JOHN P. MURTHA 3 PAVILION UPMC-JAMESON MEMORIAL HOSP. 3 UPMC- PASSAVANT HOSP. 2 UPMC-ARNOLD PALMER PAVILION 2 UPMC CANCER CENTRE AT UPMC 1 NORTHWEST UPMC-HERITAGE VALLEY HEALTH SYSTEM- 1 MEDICAL CTR, (BEAVER) UPMC-MCKEESPORT HOSP. 1 UPMC-THE WASHINGTON HOSP. 1 EMORY UNIV. 17 EMORY UNIV. 16 PIEDMONT HOSP. 1 WASHINGTON UNIV. 17 WASHINGTON UNIV. 9 COMMUNITY HOSP.S OF INDIANA REGIONAL 3 CANCER CARE NORTH NORTHWESTERN MEMORIAL HOSP. 3 CANCER INSTITUTE OF CAPE GIRARDEAU 1 METHODIST MEDICAL CTR OF ILLINOIS 1 MAYO CLINIC 15 JOE ARRINGTON CANCER RESEARCH & 4 TREATMENT CTR FLORIDA RADIATION ONCOLOGY GROUP / 3 BAPTIST REGIONAL ICON- CANCER CTR OF PUTNAM 3 ICON- FLAGLER CANCER CTR 1 ICON- FLORIDA CANCER CTR-BEACHES 1 ICON- SOUTHSIDE CANCER CTR 1 POUDRE VALLEY RADIATION ONCOLOGY 1 YAKIMA VALLEY MEMORIAL HOSP. 1 ROSWELL PARK CANCER INSTITUTE 14 ALLEGHENY-SINGER RESEARCH INSTITUTE 8 ANNE ARUNDEL MEDICAL CTR 4 ARMSTRONG COUNTY MEMORIAL HOSP. 1 INTERCOMMUNITY CANCER CTR 1 UNIV. OF MARYLAND MEDICAL SYSTEMS 12 RHODE ISLAND HOSP. 4 UNIV. OF CHICAGO 4 UNIV. OF MARYLAND MEDICAL SYSTEMS 3 INOVA ALEXANDRIA HOSP. 1 WAYNE STATE UNIV.-KARMANOS CANCER 11 INSTITUTE CLARIAN HEALTH PARTNERS, INC. 6 ST. VINCENT HOSP. AND HEALTH CARE CTRS, 3 INC. NORTHWEST COMMUNITY HOSP. 2 UNIV. OF UTAH HEALTH SCIENCE CTR 9 DARTMOUTH HITCHCOCK MEDICAL CTR 8 DARTMOUTH HITCHCOCK MEDICAL CTR 4 UNIV. OF VERMONT 3 NAVAL MEDICAL CTR/PORTSMOUTH 1 RADIOLOGICAL ASSOCIATES OF SACRAMENTO 8 BAYSTATE HEALTH 3 RADIOLOGICAL ASSOCIATES OF 2 SACRAMENTO SOLANO RADIATION ONCOLOGY CTR 2 MERCY GENERAL RADIATION ONCOLOGY 1 CTR

January 2011 0825-7 FOX CHASE CANCER CTR 7 READING HOSP. AND MEDICAL CTR 4 FOX CHASE CANCER CTR-BUCKINGHAM 1 RIVERVIEW MEDICAL CTR/RIVERVIEW 1 REGIONAL CANCER CTR THE SCHIFFLER CANCER CTR 1 CENTRE HOSP.IER DE L`UNIVERSITÉ DE MONTRÉAL (CH CROSS CANCER INSTITUTE 4 ALLAN BLAIR CANCER CENTRE 4 H. LEE MOFFITT CANCER CTR & RESEARCH 4 INSTITUTE NORTHEAST GEORGIA MEDICAL CTR 3 BROWARD GENERAL MEDICAL CTR 1 MCGILL UNIV. 4 5 UNIV. OF ALABAMA AT BIRMINGHAM MEDICAL 4 CTR ST. ALPHONSUS REGIONAL MEDICAL CTR 3 THE REGIONAL CANCER CTR AT SINGING 1 RIVER HOSP. SYSTEM AKRON CITY HOSP. 3 AKRON CITY HOSP. 2 SUMMA HEALTH SYSTEM BARBERTON HOSP. 1 UNIV. OF COLORADO DENVER 2 STATE UNIV. OF N Y AT STONY BROOK 2 MASSACHUSETTS GENERAL HOSP. 1 NORTHEAST RADIATION ONCOLOGY CTR 1 NORTHEAST RADIATION ONCOLOGY CTR 1 UNIV. OF WESTERN ONTARIO 1 NORTHEASTERN ONTARIO REGIONAL 1 CANCER CENTRE RTOG CCOP Members and Components (n=113) SOUTHEAST CANCER CONTROL CONSORTIUM, 33 INC., CCOP CAROLINAS MEDICAL CENTER 16 RALEIGH HEMATOLOGY ONCOLOGY 6 ASSOCIATES FORSYTH REGIONAL MEDICAL CENTER 4 MEMORIAL MEDICAL CENTER 3 MEMORIAL MISSION-ST. JOSEPH`S 3 PRESBYTERIAN HOSPITAL 1 MICHIGAN CANCER RESEARCH CONSORTIUM 19 CCOP SPARROW REGIONAL CANCER CENTER 7 ST. JOSEPH MERCY HOSPITAL 7 GENESYS REGIONAL MEDICAL CENTER 2 OAKWOOD HOSPITAL 1 ST. MARY`S MEDICAL CENTER 1 WEBBER CANCER CENTER 1 NORTHERN INDIANA CANCER RESEARCH CONSORTIUM CCOP METRO-MN CCOP 6 NORTH MEMORIAL MEDICAL CENTER 4 MAPLEWOOD CANCER CENTER 2 VIRGINIA MASON CCOP 6 KANSAS CITY CCOP 5 9 NEVADA CANCER RESEARCH FOUNDATION 5 CCOP NEVADA CANCER RESEARCH FOUNDATION 4 CCOP RENOWN REGIONAL MEDICAL CENTER 1 MAIN LINE CCOP 4 BRYN MAWR HOSPITAL 3 LANKENAU HOSPITAL 1 ST. VINCENT REGIONAL CANCER CENTER CCOP 4 ST. VINCENT REGIONAL CANCER CENTER 3 CCOP ST. MARY'S HOSPITAL MEDICAL CENTER 1 UPSTATE CAROLINA CCOP - GIBBS REGIONAL CANCER CENT COLUMBIA RIVER CCOP 3 PROVIDENCE PORTLAND MEDICAL CENTER 3 GULF COAST MB-CCOP - MOBILE INFIRMARY 3 MEDICAL CENT CANCER CENTER AT PROVIDENCE HOSPITAL 3 KALAMAZOO CCOP-WEST MICHIGAN CANCER CENTER GEISINGER MEDICAL CENTER CCOP 2 4 3

January 2011 0825-8 MONTANA CANCER CONSORTIUM CCOP 2 BILLINGS CLINIC CANCER CENTER 2 TOLEDO COMMUNITY HOSPITAL ONCOLOGY 2 PROGRAM CCOP FLOWER HOSPITAL 1 MERCY CANCER CENTER AT ST. ANN 1 BAY AREA TUMOR INSTITUTE CCOP 1 BEAUMONT CCOP 1 JOHN H. STROGER, JR., HOSPITAL OF COOK COUNTY MBCC 1 FLORIDA HOSPITAL 7 CALGB (n=7) CTSU (n=32) ERLANGER HEALTH SYSTEM 6 IOWA METHODIST MEDICAL CENTER 5 LANCASTER GENERAL HOSPITAL 3 LEHIGH VALLEY HOSPITAL 3 MEMORIAL REGIONAL HOSPITAL 2 PROVIDENCE ALASKA MEDICAL CENTER 2 WESLEY MEDICAL CENTER 2 ALEGENT HEALTH IMMANUEL MEDICAL CENTER 1 FLORIDA HOSPITAL CANCER INSTITUTION 1 LEGACY GOOD SAMARITAN MEDICAL CENTER MEMORIAL MEDICAL CENTER 1 MERCY HOSPITAL MEDICAL CNTR 1 MERCY MEDICAL CENTER 1 MERITCARE HOSPITAL 1 TRINITY MEDICAL CENTER 1 VIA CHRISTI REGIONAL MEDICAL CENTER 1 1 ERLANGER HEALTH SYSTEM 4 ECOG (n=4) NCCTG (n=4) MERITCARE CLINIC BEMIDJI 1 MERITCARE HOSPITAL 1 NORTH IOWA MERCY CANCER CENTER 1 VIA CHRISTI REGIONAL MEDICAL CENTER 1 SWOG (n=3) LOUISIANA STATE UNIV HOSPITAL 1 VIA CHRISTI REGIONAL MEDICAL CENTER 1 SOUTHERN REGIONAL MEDICAL CENTER 1

January 2011 0825-9 ACOSOG (n=2) ST VINCENTS HOSPITAL 1 ST. JOSEPH REGIONAL CANCER CENTER 1 Table 2.3 Case Status in Step 1 and 2 Registrations Total patients entered to step 1 650 Pending central pathology tissue screening 29 Not going to step 2 182 Insufficient tissue 58 Blood detected in scan 28 Patient refusal 14 Lab value out of range 13 Other complicating disease 9 Progression of disease 7 RX started after 5 weeks from surgery 7 Developed adverse events 6 Issues with insurance 6 XRT did not meet protocol requirement 5 Multifocal disease 4 Physician preference, NOS 3 Issues with scans 3 Death 1 Registered to wrong study 1 Other 17 Patients continued to step 2 registration 439 Pending eligibility 23 With on-study information 379 With adverse event information for concurrent RT+TMZ 289 Table 2.4 Cases with Pending Eligibility (n=23) Reason n % Pending - Verifying pre-op and post-op scan 8 35 Pending - Verifying surgery 6 26 Pending - Verifying severe active co-morbidity 3 13 Pending - Verifying KPS 3 13 Pending - Verifying post-op date 2 9 Pending - Verifying age 1 4

January 2011 0825-10 Table 2.5 Case Status Relative to Randomization in Step 3 Patients continued to step 2 registration 439 Total patients randomized to step 3 registration 416 Pending randomization 10 Not randomized 13 Patient refusal 2 Physician preference, NOS 1 Other complicating disease 1 Off-protocol RT 1 Developed adverse events 1 Other 7 Table 2.6 Case Status for Randomized Patients Arm 1 Arm 2 Total Total patients entered 205 211 416 Eligible/pending 205 211 416 With on-study information 180 185 365 With adverse event information for - - 270 concurrent RT+TMZ+BEV/placebo With adverse event information for the adjuvant stage - - 219 II. Pretreatment Characteristics: Table 3.1 Pretreatment Characteristics Pre-randomized (step 2) (n=379) Arm 1 (n=180) Randomized (step 3) Arm 2 (n=185) Age (years) Median 58 57 59 Min - Max 19-82 19-82 26-82 Q1 - Q3 51-64 51-64 52-65 <50 73 ( 19.3%) 35 ( 19.4%) 34 ( 18.4%) 50 306 ( 80.7%) 145 ( 80.6%) 151 ( 81.6%) Gender Male 223 ( 58.8%) 107 ( 59.4%) 108 ( 58.4%) Female 156 ( 41.2%) 73 ( 40.6%) 77 ( 41.6%) Race American Indian/Alaska Native 1 ( 0.3%) 1 ( 0.6%) 0 ( 0.0%) Asian 3 ( 0.8%) 2 ( 1.1%) 1 ( 0.5%) Black or African American 8 ( 2.1%) 5 ( 2.8%) 3 ( 1.6%) White 365 ( 96.3%) 170 ( 94.4%) 181 ( 97.8%) Unknown or not reported 2 ( 0.5%) 2 ( 1.1%) 0 ( 0.0%)

January 2011 0825-11 Table 3.1 Pretreatment Characteristics Pre-randomized (step 2) (n=379) Arm 1 (n=180) Randomized (step 3) Arm 2 (n=185) Ethnicity Hispanic or Latino 12 ( 3.2%) 6 ( 3.3%) 6 ( 3.2%) Not Hispanic or Latino 346 ( 91.3%) 164 ( 91.1%) 168 ( 90.8%) Unknown (Individuals not reporting ethnicity) 21 ( 5.5%) 10 ( 5.6%) 11 ( 5.9%) KPS 70-80 145 ( 38.3%) 70 ( 38.9%) 70 ( 37.8%) 90-100 231 ( 60.9%) 109 ( 60.6%) 113 ( 61.1%) Pending 3 ( 0.8%) 1 ( 0.6%) 2 ( 1.1%) Surgery Subtotal 141 ( 37.2%) 67 ( 37.2%) 67 ( 36.2%) Total (gross) 223 ( 58.8%) 105 ( 58.3%) 111 ( 60.0%) Other 10 ( 2.6%) 5 ( 2.8%) 5 ( 2.7%) Pending 5 ( 1.3%) 3 ( 1.7%) 2 ( 1.1%) Neurologic Function No symptoms 124 ( 32.7%) 58 ( 32.2%) 63 ( 34.1%) Minor symptoms 177 ( 46.7%) 84 ( 46.7%) 85 ( 45.9%) Moderate symptoms 78 ( 20.6%) 38 ( 21.1%) 37 ( 20.0%) MGMT Status* Methylated - 43 ( 23.9%) 44 ( 23.8%) Unmethylated - 134 ( 74.4%) 136 ( 73.5%) Invalid - 3 ( 1.7%) 5 ( 2.7%) Molecular Profile* Favorable - 39 ( 21.7%) 46 ( 24.9%) Unfavorable - 126 ( 70.0%) 124 ( 67.0%) Indeterminate - 13 ( 7.2%) 15 ( 8.1%) Failed - 2 ( 1.1%) 0 ( 0.0%) RPA class III 48 ( 12.7%) 26 ( 14.4%) 19 ( 10.3%) IV 168 ( 44.3%) 77 ( 42.8%) 87 ( 47.0%) V 148 ( 39.1%) 68 ( 37.8%) 73 ( 39.5%) Pending 15 ( 4.0%) 9 ( 5.0%) 6 ( 3.2%) IMRT Planned No 97 ( 25.6%) 43 ( 23.9%) 51 ( 27.6%) Yes 282 ( 74.4%) 137 ( 76.1%) 134 ( 72.4%) * Stratification factor. Ql = first quartile; Q3 = third quartile. RPA = Recursive Partitioning Analysis.

January 2011 0825-12 Table 3.2 Gender/Ethnicity/Race Distributions Sex/Gender Ethnic Category Females Males Total Hispanic or Latino 5 7 12 Not Hispanic or Latino 139 207 346 Unknown (Individuals not reporting ethnicity) 12 9 21 Ethnic Category: Total of All Subjects 156 223 379 Racial Category American Indian/Alaska Native 1 0 1 Asian 2 1 3 Black or African American 6 2 8 Unknown or not reported 1 1 2 White 146 219 365 Racial Category: Total of All Subjects 156 223 379 Table 3.3 Pretreatment PRO-QOL Compliance* (n=379) Consented to PRO-QOL collection 325 ( 85.8%) Did not consent to PRO-QOL collection 54 ( 14.2%) HVLT (n=325) Completed, prior to start of treatment 303 ( 93.2%) Completed, after start of treatment 7 ( 2.2%) Not tested 3 ( 0.9%) Discontinued 4 ( 1.2%) Form not received 8 ( 2.5%) COWA (n=325) Completed, prior to start of treatment 303 ( 93.2%) Completed, after start of treatment 7 ( 2.2%) Not tested 4 ( 1.2%) Discontinued 3 ( 0.9%) Form not received 8 ( 2.5%) Trail A (n=325) Completed, prior to start of treatment 303 ( 93.2%) Completed, after start of treatment 7 ( 2.2%) Not tested 3 ( 0.9%) Discontinued 4 ( 1.2%) Form not received 8 ( 2.5%) Trail B (n=325) Completed, prior to start of treatment 275 ( 84.6%) Completed, after start of treatment 7 ( 2.2%) Not tested 5 ( 1.5%) Discontinued 29 ( 8.9%) Reason unknown 1 ( 0.3%) Form not received 8 ( 2.5%)

January 2011 0825-13 Table 3.3 Pretreatment PRO-QOL Compliance* (n=379) EORTC QLQ-C30 (n=325) Completed, prior to start of treatment 296 ( 91.1%) Completed, after start of treatment 9 ( 2.8%) Not completed, institution error 2 ( 0.6%) Not completed, patient refusal 2 ( 0.6%) Not completed, patient refusal due to illness 2 ( 0.6%) Not completed, unknown 1 ( 0.3%) Form not received 13 ( 4.0%) M.D. Anderson Symptom Inventory (n=325) Completed, prior to start of treatment 289 ( 88.9%) Completed, after start of treatment 10 ( 3.1%) Not completed, institution error 6 ( 1.8%) Not completed, patient refusal 1 ( 0.3%) Not completed, patient refusal due to illness 1 ( 0.3%) Not completed, other reason 2 ( 0.6%) Form not received 16 ( 4.9%) PRO = patient-reported outcome; QOL = quality of life. Table 3.4 Translational Research Consent (n=379) Consented to tissue/blood/urine kept for cancer research Did not consent to tissue/blood/urine kept for cancer research Consented to tissue/blood/urine kept for medical research Did not consent to tissue/blood/urine kept for medical research 322 ( 85.0%) 57 ( 15.0%) 321 ( 84.7%) 58 ( 15.3%)

January 2011 0825-14 IV. Adverse Events: Table 4.1 Summary of Worst Adverse Event per Patient Relationship to Treatment Adverse Event Concurrent RT+TMZ (n=289) Concurrent RT+TMZ+ BEV/placebo (n=270) Adjuvant stage (n=219) Definitely, Probably, or Possibly Worst non-hematologic 1 101 ( 34.9%) 55 ( 20.4%) 42 ( 19.2%) 2 77 ( 26.6%) 116 ( 43.0%) 82 ( 37.4%) 3 24 ( 8.3%) 33 ( 12.2%) 47 ( 21.5%) 4 1 ( 0.3%) 11 ( 4.1%) 11 ( 5.0%) 5 0 ( 0.0%) 2 ( 0.7%) 5 ( 2.3%) Worst overall 1 100 ( 34.6%) 45 ( 16.7%) 30 ( 13.7%) 2 76 ( 26.3%) 104 ( 38.5%) 75 ( 34.2%) 3 31 ( 10.7%) 48 ( 17.8%) 69 ( 31.5%) 4 3 ( 1.0%) 30 ( 11.1%) 17 ( 7.8%) 5 0 ( 0.0%) 2 ( 0.7%) 5 ( 2.3%) Any Worst non-hematologic 1 84 ( 29.1%) 46 ( 17.0%) 28 ( 12.8%) 2 96 ( 33.2%) 119 ( 44.1%) 84 ( 38.4%) 3 40 ( 13.8%) 44 ( 16.3%) 65 ( 29.7%) 4 4 ( 1.4%) 14 ( 5.2%) 14 ( 6.4%) 5 1 ( 0.3%) 6 ( 2.2%) 7 ( 3.2%) Worst overall 1 83 ( 28.7%) 39 ( 14.4%) 21 ( 9.6%) 2 95 ( 32.9%) 104 ( 38.5%) 75 ( 34.2%) 3 46 ( 15.9%) 58 ( 21.5%) 81 ( 37.0%) 4 7 ( 2.4%) 31 ( 11.5%) 20 ( 9.1%) 5 1 ( 0.3%) 6 ( 2.2%) 7 ( 3.2%) Includes adverse events where relationship to protocol treatment is missing.

January 2011 0825-15 Table 4.2 Concurrent RT+TMZ Stage Number of Patients with an Adverse Event by Category, Term, and Definitely, Probably, or Possibly Related to Protocol Treatment (n=289) Category Term 1 2 3 4 5 ALLERGY/IMMUNOLOGY 0 1 0 0 0 Hypersensitivity 0 1 0 0 0 AUDITORY/EAR 4 1 0 0 0 Ear disorder 2 0 0 0 0 Hearing loss 2 0 0 0 0 Tinnitus 0 1 0 0 0 BLOOD/BONE MARROW 47 12 12 2 0 Blood disorder 1 0 0 0 0 CD4 lymphocytes decreased 1 0 1 0 0 Hemoglobin decreased 31 2 1 0 0 Hemolysis 2 0 0 0 0 Leukopenia 7 1 2 0 0 Lymphopenia 8 9 8 0 0 Neutrophil count decreased 9 1 2 1 0 Platelet count decreased 19 1 2 2 0 CARDIAC GENERAL 1 0 0 0 0 Hypotension 1 0 0 0 0 COAGULATION 0 0 1 0 0 INR increased 0 0 1 0 0 CONSTITUTIONAL SYMPTOMS 89 35 6 0 0 Chills 1 0 0 0 0 Fatigue 85 32 6 0 0 Fever 2 0 0 0 0 Insomnia 13 7 0 0 0 Sweating 2 0 0 0 0 Weight loss 5 0 0 0 0 DERMATOLOGY/SKIN 74 24 1 0 0 Acne 0 1 0 0 0 Alopecia 55 19 0 0 0 Dermatitis radiation 17 3 0 0 0 Dry skin 1 0 0 0 0 Erythema multiforme 3 0 0 0 0 Pruritus 6 0 0 0 0 Radiation recall reaction (dermatologic) 16 1 0 0 0 Rash desquamating 0 1 0 0 0 Skin disorder 1 0 0 0 0 Skin hyperpigmentation 1 0 0 0 0 Wound dehiscence 1 0 1 0 0

January 2011 0825-16 Table 4.2 Concurrent RT+TMZ Stage Number of Patients with an Adverse Event by Category, Term, and Definitely, Probably, or Possibly Related to Protocol Treatment (n=289) Category Term 1 2 3 4 5 ENDOCRINE 4 1 0 0 0 Cushingoid 0 1 0 0 0 Endocrine disorder 1 0 0 0 0 Hot flashes 3 0 0 0 0 GASTROINTESTINAL 83 29 1 0 0 Anorexia 18 4 0 0 0 Colonic perforation 0 0 1 0 0 Constipation 33 12 0 0 0 Diarrhea 3 2 0 0 0 Dry mouth 4 1 0 0 0 Dyspepsia 3 1 0 0 0 Dysphagia 2 1 0 0 0 Gastrointestinal disorder 1 0 0 0 0 Mucositis oral 3 0 0 0 0 Nausea 57 12 0 0 0 Pharyngeal examination abnormal 1 0 0 0 0 Taste alteration 10 6 0 0 0 Vomiting 12 4 0 0 0 HEMORRHAGE/BLEEDING 1 0 0 0 0 Respiratory tract hemorrhage 1 0 0 0 0 INFECTION 1 7 3 0 0 Gingival infection [with normal or 1-2 ANC] 0 1 0 0 0 Gingival infection [with unknown ANC] 0 1 0 0 0 Infection [other] 0 1 0 0 0 Lip infection [with unknown ANC] 0 1 0 0 0 Mucosal infection [with normal or 1-2 ANC] 1 0 0 0 0 Opportunistic infection 0 1 0 0 0 Peripheral nerve infection [with normal or 1-2 ANC] 0 1 0 0 0 Upper aerodigestive tract infection [with normal or 1-0 1 1 0 0 2 ANC] Urinary tract infection [with normal or 1-2 ANC] 0 0 1 0 0 Wound infection [with unknown ANC] 0 0 1 0 0 LYMPHATICS 7 2 1 0 0 Edema limbs 2 2 1 0 0 Localized edema [head and neck] 5 0 0 0 0 METABOLIC/LABORATORY 46 7 12 0 0 Alanine aminotransferase increased 20 1 6 0 0 Alkaline phosphatase increased 4 0 0 0 0 Aspartate aminotransferase increased 8 3 4 0 0 Creatinine increased 7 0 0 0 0 Gamma-glutamyltransferase increased 0 0 2 0 0 Hyperbilirubinemia 0 1 0 0 0 Hypercalcemia 1 0 0 0 0

January 2011 0825-17 Table 4.2 Concurrent RT+TMZ Stage Number of Patients with an Adverse Event by Category, Term, and Definitely, Probably, or Possibly Related to Protocol Treatment (n=289) Category Term 1 2 3 4 5 Hyperglycemia 13 4 2 0 0 Hyperkalemia 2 0 0 0 0 Hypermagnesemia 1 0 0 0 0 Hypernatremia 1 0 0 0 0 Hypoalbuminemia 8 2 0 0 0 Hypocalcemia 8 0 0 0 0 Hypokalemia 3 0 1 0 0 Hyponatremia 9 0 3 0 0 Laboratory test abnormal 10 1 0 0 0 MUSCULOSKELETAL/SOFT TISSUE 6 3 0 0 0 Gait abnormal 0 1 0 0 0 Muscle weakness 3 1 0 0 0 Muscle weakness lower limb 2 1 0 0 0 Musculoskeletal disorder 1 0 0 0 0 NEUROLOGY 24 16 3 0 0 Acoustic nerve disorder NOS 0 1 0 0 0 Agitation 1 0 0 0 0 Anxiety 2 3 0 0 0 Ataxia 2 4 0 0 0 Depressed level of consciousness 1 1 1 0 0 Depression 1 2 0 0 0 Dizziness 6 3 0 0 0 Memory impairment 4 0 0 0 0 Mental status changes 1 0 0 0 0 Olfactory nerve disorder 1 1 0 0 0 Peripheral motor neuropathy 5 3 1 0 0 Peripheral sensory neuropathy 4 2 0 0 0 Personality change 1 0 0 0 0 Seizure 0 3 1 0 0 Speech disorder 2 1 0 0 0 Tremor 2 0 0 0 0 OCULAR/VISUAL 11 0 0 0 0 Diplopia 1 0 0 0 0 Photophobia 1 0 0 0 0 Vision blurred 9 0 0 0 0 PAIN 46 16 0 0 0 Abdominal pain 2 0 0 0 0 Ear pain 1 1 0 0 0 Headache 39 14 0 0 0 Joint pain 3 1 0 0 0 Myalgia 6 1 0 0 0 Pain [other] 2 0 0 0 0 Pain in extremity 1 0 0 0 0

January 2011 0825-18 Table 4.2 Concurrent RT+TMZ Stage Number of Patients with an Adverse Event by Category, Term, and Definitely, Probably, or Possibly Related to Protocol Treatment (n=289) Category Term 1 2 3 4 5 PULMONARY/UPPER RESPIRATORY 6 2 0 0 0 Cough 2 0 0 0 0 Dyspnea 3 0 0 0 0 Hiccough 0 1 0 0 0 Nasal congestion 1 0 0 0 0 Respiratory disorder 0 1 0 0 0 RENAL/GENITOURINARY 3 3 1 0 0 Cystitis 0 1 0 0 0 Urinary frequency 3 2 1 0 0 Urinary retention 0 1 0 0 0 SEXUAL/REPRODUCTIVE FUNCTION 1 0 0 0 0 Libido decreased 1 0 0 0 0 VASCULAR 0 1 3 1 0 Thrombosis 0 0 2 1 0 Vascular access complication 0 1 1 0 0 PENDING CLARIFICATION OF TERM 2 0 0 0 0 Includes adverse events where relationship to protocol treatment is missing. Adverse events were graded with CTCAE version 3.0. Table 4.3 Concurrent RT+TMZ Stage Number of Patients with an Adverse Event by Category and Any Relationship to Protocol Treatment (n=289) Category 1 2 3 4 5 Allergy/immunology 0 1 0 0 0 Auditory/ear 5 3 0 0 0 Blood/bone marrow 54 12 12 3 0 Cardiac arrhythmia 0 1 1 0 0 Cardiac general 4 2 0 1 0 Coagulation 0 0 1 0 0 Constitutional symptoms 97 38 6 1 0 Death 0 0 0 0 1 Dermatology/skin 82 25 2 0 0 Endocrine 4 3 0 0 0 Gastrointestinal 89 35 2 0 0 Hemorrhage/bleeding 2 1 0 0 0

January 2011 0825-19 Table 4.3 Concurrent RT+TMZ Stage Number of Patients with an Adverse Event by Category and Any Relationship to Protocol Treatment (n=289) Category 1 2 3 4 5 Infection 2 10 4 1 0 Lymphatics 14 4 1 0 0 Metabolic/laboratory 55 12 21 0 0 Musculoskeletal/soft tissue 9 5 1 0 0 Neurology 36 31 7 0 0 Ocular/visual 24 2 0 0 0 Pain 62 23 1 0 0 Pulmonary/upper respiratory 14 2 1 0 0 Renal/genitourinary 5 5 1 0 0 Sexual/reproductive function 1 0 0 0 0 Vascular 1 2 7 1 0 Pending clarification of term 2 0 0 0 0 Includes adverse events where relationship to protocol treatment is missing. Adverse events were graded with CTCAE version 3.0. Table 4.4 Concurrent RT+TMZ+BEV/Placebo Stage Number of Patients with an Adverse Event by Category, Term, and Definitely, Probably, or Possibly Related to Protocol Treatment (n=270) Category Term 1 2 3 4 5 ALLERGY/IMMUNOLOGY 2 1 0 0 0 Allergic rhinitis 2 0 0 0 0 Hypersensitivity 0 1 0 0 0 AUDITORY/EAR 10 5 0 0 0 Ear disorder 3 0 0 0 0 External ear inflammation 2 1 0 0 0 Hearing loss 3 2 0 0 0 Tinnitus 2 2 0 0 0 BLOOD/BONE MARROW 57 22 27 20 0 Blood disorder 2 1 0 0 0 Bone marrow hypocellular 0 0 0 1 0 CD4 lymphocytes decreased 2 1 4 0 0 Hemoglobin decreased 32 4 1 0 0 Hemolysis 1 0 1 0 0 Leukopenia 16 7 9 2 0 Lymphopenia 6 11 19 5 0 Neutrophil count decreased 12 4 5 10 0 Platelet count decreased 39 10 11 11 0

January 2011 0825-20 Table 4.4 Concurrent RT+TMZ+BEV/Placebo Stage Number of Patients with an Adverse Event by Category, Term, and Definitely, Probably, or Possibly Related to Protocol Treatment (n=270) Category Term 1 2 3 4 5 CARDIAC ARRHYTHMIA 1 0 1 0 0 Sinus tachycardia 1 0 0 0 0 Syncope vasovagal 0 0 1 0 0 CARDIAC GENERAL 2 6 1 0 0 Hypertension 1 5 1 0 0 Hypotension 1 1 0 0 0 COAGULATION 0 0 1 0 0 INR increased 0 0 1 0 0 CONSTITUTIONAL SYMPTOMS 78 79 5 1 0 Chills 2 0 0 0 0 Fatigue 72 74 6 0 0 General symptom 0 1 0 0 0 Insomnia 13 5 1 0 0 Obesity 0 0 0 1 0 Sweating 2 0 0 0 0 Weight gain 1 0 0 0 0 Weight loss 13 2 0 0 0 DEATH 0 0 0 0 2 Death 0 0 0 0 1 Disease progression 0 0 0 0 1 DERMATOLOGY/SKIN 80 55 2 1 0 Acne 2 1 0 0 0 Alopecia 66 42 1 0 0 Dermatitis radiation 30 3 0 0 0 Dry skin 3 2 0 0 0 Erythema multiforme 4 3 0 1 0 Pruritus 11 1 2 0 0 Radiation recall reaction (dermatologic) 21 8 0 0 0 Rash desquamating 3 2 1 0 0 Skin disorder 1 0 0 0 0 Skin hyperpigmentation 9 0 0 0 0 Wound dehiscence 0 0 1 0 0 ENDOCRINE 2 0 0 0 0 Endocrine disorder 2 0 0 0 0 GASTROINTESTINAL 74 47 3 0 0 Anorexia 30 11 0 0 0 Constipation 27 22 1 0 0 Dehydration 0 3 0 0 0 Diarrhea 8 2 0 0 0 Dry mouth 7 1 0 0 0

January 2011 0825-21 Table 4.4 Concurrent RT+TMZ+BEV/Placebo Stage Number of Patients with an Adverse Event by Category, Term, and Definitely, Probably, or Possibly Related to Protocol Treatment (n=270) Category Term 1 2 3 4 5 Dyspepsia 5 0 0 0 0 Ear, nose and throat examination abnormal 1 1 0 0 0 Esophagoscopy abnormal 0 1 0 0 0 Flatulence 1 0 0 0 0 Gastrointestinal disorder 2 2 0 0 0 Mucositis oral 3 2 0 0 0 Nausea 46 19 2 0 0 Pharyngeal examination abnormal 1 0 0 0 0 Salivary gland disorder 1 0 0 0 0 Taste alteration 17 12 0 0 0 Vomiting 3 3 1 0 0 HEMORRHAGE/BLEEDING 13 2 0 0 0 Hemorrhage 1 0 0 0 0 Hemorrhage nasal 10 0 0 0 0 Intracranial hemorrhage 1 1 0 0 0 Petechiae 0 1 0 0 0 Respiratory tract hemorrhage 1 0 0 0 0 INFECTION 4 15 1 0 0 Conjunctivitis infective [with normal or 1-2 ANC] 1 0 0 0 0 Device related infection [with unknown ANC] 0 1 0 0 0 Febrile neutropenia 0 1 0 0 0 Gingival infection [with normal or 1-2 ANC] 0 1 0 0 0 Gingival infection [with unknown ANC] 1 0 0 0 0 Infection [other] 0 4 0 0 0 Lip infection [with unknown ANC] 0 1 0 0 0 Mucosal infection [with normal or 1-2 ANC] 1 1 0 0 0 Opportunistic infection 0 1 0 0 0 Otitis externa [with normal or 1-2 ANC] 0 1 0 0 0 Otitis externa [with unknown ANC] 0 1 0 0 0 Otitis media [with normal or 1-2 ANC] 0 1 0 0 0 Pneumonia [with unknown ANC] 0 0 1 0 0 Upper respiratory infection [with normal or 1-2 0 1 0 0 0 ANC] Urinary tract infection [with unknown ANC] 1 0 0 0 0 Vaginal infection [with normal or 1-2 ANC] 0 1 0 0 0 LYMPHATICS 16 3 1 1 0 Edema limbs 9 1 0 1 0 Localized edema [head and neck] 7 1 1 0 0 Visceral edema 0 1 0 0 0 METABOLIC/LABORATORY 57 14 10 3 0 Alanine aminotransferase increased 23 5 2 2 0 Alkaline phosphatase increased 7 0 0 0 0 Aspartate aminotransferase increased 19 4 1 0 0 Creatinine increased 12 1 0 0 0

January 2011 0825-22 Table 4.4 Concurrent RT+TMZ+BEV/Placebo Stage Number of Patients with an Adverse Event by Category, Term, and Definitely, Probably, or Possibly Related to Protocol Treatment (n=270) Category Term 1 2 3 4 5 Gamma-glutamyltransferase increased 0 0 2 0 0 Hyperbilirubinemia 3 1 0 0 0 Hypercalcemia 1 0 0 0 0 Hyperglycemia 19 5 2 0 0 Hyperkalemia 2 1 0 0 0 Hypermagnesemia 2 0 0 0 0 Hypernatremia 1 0 0 0 0 Hypoalbuminemia 14 2 0 0 0 Hypocalcemia 5 2 0 0 0 Hypokalemia 7 0 1 1 0 Hyponatremia 14 0 2 0 0 Laboratory test abnormal 6 1 1 0 0 Proteinuria 4 1 0 0 0 MUSCULOSKELETAL/SOFT TISSUE 7 7 2 0 0 Gait abnormal 1 0 0 0 0 Muscle weakness 4 4 1 0 0 Muscle weakness left-sided 0 1 0 0 0 Muscle weakness lower limb 2 2 1 0 0 Musculoskeletal disorder 1 0 0 0 0 NEUROLOGY 26 19 6 1 0 Acoustic nerve disorder NOS 0 1 0 0 0 Agitation 3 0 0 0 0 Anxiety 5 2 0 0 0 Ataxia 3 3 1 0 0 Cognitive disturbance 0 0 1 0 0 Confusion 1 1 0 0 0 Depression 3 4 0 0 0 Dizziness 18 1 1 0 0 Ischemia cerebrovascular 0 1 0 0 0 Memory impairment 3 1 0 0 0 Mental status changes 0 1 0 0 0 Neurological disorder NOS 1 0 0 0 0 Olfactory nerve disorder 1 2 0 0 0 Optic nerve disorder 0 1 0 0 0 Peripheral motor neuropathy 3 5 1 0 0 Peripheral sensory neuropathy 7 0 1 0 0 Seizure 1 3 2 1 0 Speech disorder 0 1 0 0 0 Tremor 2 0 0 0 0 OCULAR/VISUAL 8 2 0 0 0 Dry eye syndrome 1 0 0 0 0 Eye disorder 0 1 0 0 0 Photophobia 1 0 0 0 0 Vision blurred 5 1 0 0 0 Watering eyes 1 0 0 0 0

January 2011 0825-23 Table 4.4 Concurrent RT+TMZ+BEV/Placebo Stage Number of Patients with an Adverse Event by Category, Term, and Definitely, Probably, or Possibly Related to Protocol Treatment (n=270) Category Term 1 2 3 4 5 PAIN 41 23 3 1 0 Abdominal pain 4 0 1 0 0 Anal pain 0 1 0 0 0 Back pain 1 1 0 0 0 Chest wall pain 0 1 0 0 0 Ear pain 3 2 0 0 0 Esophageal pain 1 0 0 0 0 Eye pain 2 0 0 0 0 Gingival pain 1 0 0 0 0 Headache 33 17 1 0 0 Joint pain 2 2 1 0 0 Myalgia 5 2 1 0 0 Oral pain 1 0 0 0 0 Pain [other] 2 0 0 0 0 Pain in extremity 1 0 0 0 0 Pain of skin 0 0 0 1 0 Pelvic pain 1 0 0 0 0 Scalp pain 2 0 0 0 0 PULMONARY/UPPER RESPIRATORY 8 1 1 1 0 Cough 2 0 1 0 0 Dyspnea 5 1 0 1 0 Hiccough 1 0 0 0 0 Voice alteration 2 0 0 0 0 RENAL/GENITOURINARY 3 2 1 0 0 Cystitis 0 1 0 0 0 Urinary frequency 3 0 1 0 0 Urinary incontinence 0 1 0 0 0 Urinary retention 1 0 0 0 0 VASCULAR 1 1 5 6 1 Thrombosis 1 1 4 5 1 Vascular access complication 0 0 1 1 0 Vascular disorder 0 0 1 0 0 PENDING CLARIFICATION OF TERM 3 1 0 0 0 Includes adverse events where relationship to protocol treatment is missing. Adverse events were graded with CTCAE version 3.0.

January 2011 0825-24 Table 4.5 Concurrent RT+TMZ+BEV/Placebo Stage Number of Patients with an Adverse Event by Category and Any Relationship to Protocol Treatment (n=270) Category 1 2 3 4 5 Allergy/immunology 6 1 0 0 0 Auditory/ear 11 10 0 0 0 Blood/bone marrow 59 22 27 20 0 Cardiac arrhythmia 2 0 1 0 0 Cardiac general 4 8 1 0 0 Coagulation 1 0 1 0 0 Constitutional symptoms 82 82 7 1 0 Death 0 0 0 0 2 Dermatology/skin 81 59 4 2 0 Endocrine 2 3 0 0 0 Gastrointestinal 77 55 6 0 1 Hemorrhage/bleeding 14 4 0 0 0 Infection 4 21 2 0 0 Lymphatics 21 5 1 1 0 Metabolic/laboratory 72 21 15 3 0 Musculoskeletal/soft tissue 11 13 5 1 0 Neurology 40 38 14 2 2 Ocular/visual 25 5 0 0 0 Pain 58 32 5 2 0 Pulmonary/upper respiratory 18 1 1 1 1 Renal/genitourinary 7 4 2 0 0 Vascular 1 3 7 6 1 Pending clarification of term 4 1 0 0 0 Includes adverse events where relationship to protocol treatment is missing. Adverse events were graded with CTCAE version 3.0. Table 4.6 Adjuvant Stage Number of Patients with an Adverse Event by Category, Term, and Definitely, Probably, or Possibly Related to Protocol Treatment (n=219) Category Term 1 2 3 4 5 ALLERGY/IMMUNOLOGY 3 2 0 0 0 Allergic rhinitis 3 1 0 0 0 Hypersensitivity 0 1 0 0 0 AUDITORY/EAR 4 6 1 0 0 Ear disorder 1 0 0 0 0 Hearing loss 1 3 0 0 0 Middle ear inflammation 0 1 0 0 0 Tinnitus 3 2 1 0 0

January 2011 0825-25 Table 4.6 Adjuvant Stage Number of Patients with an Adverse Event by Category, Term, and Definitely, Probably, or Possibly Related to Protocol Treatment (n=219) Category Term 1 2 3 4 5 BLOOD/BONE MARROW 50 34 35 8 0 Blood disorder 5 2 1 0 0 CD4 lymphocytes decreased 1 2 3 1 0 Hemoglobin decreased 47 5 1 0 0 Hemolysis 2 0 0 0 0 Leukopenia 35 21 12 0 0 Lymphopenia 13 20 18 5 0 Neutrophil count decreased 20 12 16 1 0 Platelet count decreased 51 21 10 2 0 CARDIAC ARRHYTHMIA 0 0 1 0 0 Atrial fibrillation 0 0 1 0 0 CARDIAC GENERAL 4 9 4 0 0 Hypertension 4 8 4 0 0 Hypotension 0 1 0 0 0 CONSTITUTIONAL SYMPTOMS 64 53 21 1 0 Chills 3 1 0 0 0 Fatigue 66 48 20 1 0 Fever 1 1 0 0 0 General symptom 5 2 0 0 0 Insomnia 13 5 0 0 0 Weight loss 13 10 2 0 0 DEATH 0 0 0 0 4 Death 0 0 0 0 3 Disease progression 0 0 0 0 1 DERMATOLOGY/SKIN 51 27 3 1 0 Acne 2 1 0 0 0 Alopecia 34 19 2 0 0 Decubitus ulcer 1 0 0 0 0 Dermatitis radiation 2 0 0 0 0 Dry skin 3 3 0 0 0 Erythema multiforme 3 1 0 0 0 Pruritus 4 2 0 0 0 Radiation recall reaction (dermatologic) 6 2 0 0 0 Rash desquamating 2 2 1 1 0 Skin disorder 2 0 0 0 0 Skin hyperpigmentation 2 0 0 0 0 Wound dehiscence 1 2 0 0 0 ENDOCRINE 3 0 0 0 0 Endocrine disorder 3 0 0 0 0 GASTROINTESTINAL 54 65 11 0 0

January 2011 0825-26 Table 4.6 Adjuvant Stage Number of Patients with an Adverse Event by Category, Term, and Definitely, Probably, or Possibly Related to Protocol Treatment (n=219) Category Term 1 2 3 4 5 Abdominal distension 2 0 0 0 0 Anorexia 25 32 2 0 0 Cecal ulcer 0 0 1 0 0 Colonic perforation 0 0 1 0 0 Constipation 27 12 3 0 0 Dehydration 1 7 1 0 0 Diarrhea 18 3 0 0 0 Dry mouth 9 0 0 0 0 Dyspepsia 5 2 0 0 0 Dysphagia 2 0 0 0 0 Ear, nose and throat examination abnormal 0 2 0 0 0 Endoscopy large bowel abnormal 0 1 0 0 0 Gastric mucositis 0 1 0 0 0 Gastritis 0 2 0 0 0 Gastrointestinal disorder 3 1 0 0 0 Hemorrhoids 0 2 0 0 0 Ileal perforation 0 0 1 0 0 Mucositis oral 9 2 0 0 0 Nausea 48 32 2 0 0 Proctitis 0 1 0 0 0 Taste alteration 13 8 0 0 0 Vomiting 17 10 4 0 0 HEMORRHAGE/BLEEDING 20 2 1 0 0 Hemorrhage 2 0 0 0 0 Hemorrhage nasal 14 0 0 0 0 Intracranial hemorrhage 0 1 0 0 0 Lower gastrointestinal hemorrhage 2 0 0 0 0 Oral hemorrhage 6 0 0 0 0 Petechiae 1 0 0 0 0 Pharyngeal hemorrhage 1 0 0 0 0 Respiratory tract hemorrhage 1 0 0 0 0 Upper gastrointestinal hemorrhage 0 1 1 0 0 INFECTION 1 13 5 0 0 Bladder infection [with normal or 1-2 ANC] 0 2 0 0 0 Bladder infection [with unknown ANC] 0 1 0 0 0 Gingival infection [with normal or 1-2 ANC] 0 1 0 0 0 Gingival infection [with unknown ANC] 0 1 0 0 0 Infection [other] 0 2 0 0 0 Mucosal infection [with 3-4 ANC] 0 1 0 0 0 Mucosal infection [with normal or 1-2 ANC] 0 2 0 0 0 Opportunistic infection 0 0 1 0 0 Otitis externa [with 3-4 ANC] 0 1 0 0 0 Otitis media [with unknown ANC] 0 1 0 0 0 Pneumonia [with normal or 1-2 ANC] 0 0 1 0 0 Pneumonia [with unknown ANC] 0 0 1 0 0 Sinusitis [with unknown ANC] 0 2 0 0 0

January 2011 0825-27 Table 4.6 Adjuvant Stage Number of Patients with an Adverse Event by Category, Term, and Definitely, Probably, or Possibly Related to Protocol Treatment (n=219) Category Term 1 2 3 4 5 Soft tissue infection [with 3-4 ANC] 0 1 0 0 0 Tooth infection [with normal or 1-2 ANC] 0 1 0 0 0 Urinary tract infection [with unknown ANC] 0 1 1 0 0 Vaginal infection [with unknown ANC] 1 0 0 0 0 Wound infection [with normal or 1-2 ANC] 0 1 1 0 0 LYMPHATICS 8 1 0 1 0 Edema limbs 7 2 0 0 0 Localized edema [head and neck] 1 0 0 1 0 METABOLIC/LABORATORY 58 19 7 2 0 Alanine aminotransferase increased 26 3 1 0 0 Alkaline phosphatase increased 9 0 0 1 0 Alkalosis 0 0 1 0 0 Aspartate aminotransferase increased 20 3 0 0 0 Blood bicarbonate decreased 1 0 0 0 0 Creatinine increased 11 1 0 0 0 Gamma-glutamyltransferase increased 1 0 2 0 0 Glomerular filtration rate decreased 0 2 0 0 0 Hyperbilirubinemia 9 2 0 0 0 Hypercalcemia 2 0 0 0 0 Hypercholesterolemia 1 0 0 0 0 Hyperglycemia 27 7 2 0 0 Hyperkalemia 2 1 0 0 0 Hypermagnesemia 1 0 0 0 0 Hypoalbuminemia 9 1 1 0 0 Hypocalcemia 9 0 0 0 0 Hypoglycemia 1 2 0 0 0 Hypokalemia 14 0 0 0 0 Hyponatremia 11 0 1 1 0 Laboratory test abnormal 13 1 0 0 0 Proteinuria 6 3 1 0 0 MUSCULOSKELETAL/SOFT TISSUE 10 18 5 0 0 Arthritis 1 0 0 0 0 Gait abnormal 2 2 0 0 0 Muscle weakness 8 13 4 0 0 Muscle weakness left-sided 1 0 0 0 0 Muscle weakness lower limb 0 6 1 0 0 Muscle weakness trunk 0 1 0 0 0 Muscle weakness upper limb 0 1 0 0 0 Musculoskeletal disorder 1 0 0 0 0 NEUROLOGY 32 19 11 2 0 Abducens nerve disorder 0 1 0 0 0 Agitation 3 2 0 0 0 Anxiety 3 5 1 0 0 Ataxia 2 5 1 0 0

January 2011 0825-28 Table 4.6 Adjuvant Stage Number of Patients with an Adverse Event by Category, Term, and Definitely, Probably, or Possibly Related to Protocol Treatment (n=219) Category Term 1 2 3 4 5 Cognitive disturbance 2 0 0 0 0 Confusion 2 1 4 1 0 Depressed level of consciousness 1 0 1 0 0 Depression 6 5 0 0 0 Dizziness 16 1 0 0 0 Hydrocephalus 1 0 0 0 0 Ischemia cerebrovascular 0 0 1 0 0 Memory impairment 14 2 0 0 0 Mental status changes 0 1 0 0 0 Neurological disorder NOS 6 1 0 0 0 Peripheral motor neuropathy 1 5 1 1 0 Peripheral sensory neuropathy 8 1 0 0 0 Psychosis 0 0 1 0 0 Seizure 0 4 3 0 0 Speech disorder 3 3 2 0 0 Syncope 0 0 1 0 0 Tremor 4 1 0 0 0 Trigeminal nerve disorder 0 1 0 0 0 OCULAR/VISUAL 11 5 0 0 0 Diplopia 1 0 0 0 0 Eye disorder 2 2 0 0 0 Flashing vision 1 0 0 0 0 Vision blurred 3 3 0 0 0 Watering eyes 4 0 0 0 0 PAIN 43 25 5 0 0 Abdominal pain 3 4 0 0 0 Back pain 2 2 0 0 0 Bone pain 1 1 0 0 0 Chest pain 1 0 0 0 0 Ear pain 1 1 0 0 0 Eye pain 1 0 0 0 0 Gastrointestinal pain 0 0 1 0 0 Gingival pain 1 1 0 0 0 Headache 34 13 2 0 0 Joint pain 4 5 1 0 0 Myalgia 3 5 1 0 0 Neck pain 0 1 0 0 0 Oral pain 1 0 0 0 0 Pain [NOS] 1 1 0 0 0 Pain [other] 3 0 0 0 0 Pain in extremity 4 0 1 0 0 Pharyngolaryngeal pain 3 0 0 0 0 Sinus pain 1 0 0 0 0 PULMONARY/UPPER RESPIRATORY 13 5 0 2 0 Adult respiratory distress syndrome 0 0 0 1 0

January 2011 0825-29 Table 4.6 Adjuvant Stage Number of Patients with an Adverse Event by Category, Term, and Definitely, Probably, or Possibly Related to Protocol Treatment (n=219) Category Term 1 2 3 4 5 Cough 6 0 0 0 0 Dyspnea 6 1 0 1 0 Hiccough 0 1 0 0 0 Hypoxia 0 1 0 0 0 Nasal congestion 0 1 0 0 0 Respiratory disorder 2 0 0 1 0 Voice alteration 5 2 0 0 0 RENAL/GENITOURINARY 5 2 0 0 0 Urinary frequency 2 1 0 0 0 Urinary retention 0 1 0 0 0 Urine discoloration 1 0 0 0 0 Urogenital disorder 3 0 0 0 0 SEXUAL/REPRODUCTIVE FUNCTION 1 1 0 0 0 Irregular menstruation 0 1 0 0 0 Vaginal dryness 1 0 0 0 0 VASCULAR 0 1 7 6 1 Thrombosis 0 0 4 6 1 Vascular access complication 0 1 3 1 0 PENDING CLARIFICATION OF TERM 4 0 0 1 0 Includes adverse events where relationship to protocol treatment is missing. Adverse events were graded with CTCAE version 3.0. Table 4.7 Adjuvant Stage Number of Patients with an Adverse Event by Category and Any Relationship to Protocol Treatment (n=219) Category 1 2 3 4 5 Allergy/immunology 6 3 0 0 0 Auditory/ear 6 11 2 0 0 Blood/bone marrow 51 35 35 8 0 Cardiac arrhythmia 0 1 2 0 0 Cardiac general 6 13 4 0 0 Coagulation 0 1 1 0 0 Constitutional symptoms 67 56 23 2 0 Death 0 0 0 0 6 Dermatology/skin 59 33 5 1 0 Endocrine 4 5 1 0 0 Gastrointestinal 55 69 14 0 0

January 2011 0825-30 Table 4.7 Adjuvant Stage Number of Patients with an Adverse Event by Category and Any Relationship to Protocol Treatment (n=219) Category 1 2 3 4 5 Hemorrhage/bleeding 22 4 1 0 0 Infection 4 25 6 0 0 Lymphatics 15 2 0 1 0 Metabolic/laboratory 64 31 11 3 0 Musculoskeletal/soft tissue 14 22 8 0 0 Neurology 45 41 27 5 0 Ocular/visual 24 11 1 0 0 Pain 55 41 9 0 0 Pulmonary/upper respiratory 28 6 2 2 0 Renal/genitourinary 7 4 1 0 0 Sexual/reproductive function 1 1 0 0 0 Vascular 1 1 7 6 1 Pending clarification of term 4 0 0 1 0 Includes adverse events where relationship to protocol treatment is missing. Adverse events were graded with CTCAE version 3.0. Table 4.8 5 Adverse Events Case Number Category Term Relationship to Treatment Days from Start of Treatment Days from End of Treatment 27 Death Death Possible 123 14 50 Death Death Unlikely 160 21 63 Death Death Possible 72 33 89 Pulmonary/upper Pneumonitis Unlikely 44 2 respiratory 129 Neurology Depression Unrelated 58 13 134 Death Disease progression Possible 118 64 135 Death Disease progression Possible 118 14 251 Death Disease progression Unrelated 124 16 275 Neurology Encephalopathy Unlikely 52 11 283 Vascular Thrombosis Probable 77 2 288 Death Death Possible 74 5 354 Death Disease progression Unrelated 7 3 418 Gastrointestinal Appendicitis Unlikely 93 36 perforated 528 Vascular Thrombosis Possible 36 0 Adverse events were graded with CTCAE version 3.0.

January 2011 0825-31 V. Protocol Treatment Reviews: Table 5.1 Status of Protocol Treatment Reviews (n=439) Radiation therapy Contour and dose reviewed 220 ( 50.1%) Contour reviewed 2 ( 0.5%) Dose reviewed 121 ( 27.6%) Not reviewed 220 ( 50.1%) Chemotherapy Reviewed 0 ( 0.0%) Not reviewed 439 (100.0%) Table 5.2 Radiotherapy Review Tumor Volume Tumor Volume Dose Volume Analysis Score Tumor Volume Contouring Score Per protocol Acceptable variation Unacceptable variation Not evaluable Not reviewed Total Per protocol 163 (48%) 23 (7%) 15 (4%) 0 (0%) 1 (0%) 202 (59%) Acceptable variation 5 (1%) 2 (1%) 4 (1%) 0 (0%) 0 (0%) 11 (3%) Unacceptable variation 0 (0%) 0 (0%) 3 (1%) 0 (0%) 1 (0%) 4 (1%) Not evaluable 0 (0%) 0 (0%) 0 (0%) 5 (1%) 0 (0%) 5 (1%) Not reviewed 99 (29%) 9 (3%) 13 (4%) 0 (0%) 0 (0%) 121 (35%) Total 267 (78%) 34 (10%) 35 (10%) 5 (1%) 2 (1%) 343 100%) Table 5.3 Radiotherapy Review Tumor Volume by Organs at Risk Organs at Risk Contouring Score Tumor Volume Contouring Score Per protocol Acceptable variation Unacceptable variation Not evaluable Not reviewed Total Per protocol 182 (53%) 20 (6%) 0 (0%) 0 (0%) 0 (0%) 202 (59%) Acceptable variation 9 (3%) 2 (1%) 0 (0%) 0 (0%) 0 (0%) 11 (3%) Unacceptable variation 4 (1%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 4 (1%) Not evaluable 0 (0%) 0 (0%) 0 (0%) 5 (1%) 0 (0%) 5 (1%) Not reviewed 0 (0%) 0 (0%) 0 (0%) 0 (0%) 121 (35%) 121 (35%) Total 195 (57%) 22 (6%) 0 (0%) 5 (1%) 121 (35%) 343(100%)

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