6 cycles* January Opened: January 17, 2006

Transcription

1 January RTOG Protocol No: 0525 Protocol Status: Opened: January 17, 2006 Title: Phase III Trial Comparing Conventional Adjuvant Temozolomide with Dose-Intensive Temozolomide in Patients with Newly Diagnosed Glioblastoma Patient Population: Objectives: Schema: All patients must have histopathologically confirmed glioblastoma (WHO Grade IV) confirmed by central tissue evaluation. The tumor must have a supratentorial component. Tumor tissue block must be available for analysis. Primary: To determine if dose-intensifying (increasing the dose-density ) the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy as measured by overall survival. Secondary: To determine if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy as measured by progression-free survival. To determine in patients with unmethylated MGMT if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy (overall and progression-free survival) compared with patients receiving conventional temozolomide dosing. To determine in patients with methylated MGMT if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy (overall and progression-free survival) compared with patients receiving conventional temozolomide dosing. To determine if there is an association between tumor MGMT gene methylation status and treatment response. To compare and record the toxicities of the conventional and dose-intense chemotherapy regimens. To evaluate whether 6-month progression-free survival is associated with overall survival. R E G I S T E R Tissue Collection & Evaluation Radiation (60 Gy in 2 Gy fractions) Concurrent daily TMZ (qd x 49 d maximum) STRATIFY BY: RPA Class 1. III 2. IV 3. V MGMT Status 1. Methylated 2. Unmethylated 3. Unknown R A N D O M I Z E Arm 1 (Standard Arm) TMZ d 1-5 of 28-d cycle 6 cycles* Arm 2 (Experimental Arm) TMZ d 1-21 of 28-d cycle 6 cycles* Radiation 1. Standard US 2. Revised European * Up to 12 cycles may be given if the patient demonstrates continued improvement on MR scan, decreasing corticosteroid requirement, improvement in performance status, or improvement in neurologic function.

2 January Study Chairs: Mark R. Gilbert, M.D. (Medical Oncology) Patients entered through 11/04/07: Minesh Mehta, M.D. (Radiation Oncology) Study 755 Ken Aldape, M.D. (Neuropathology and Correlative Biology) RTOG 634 Arnab Chakravarti, M.D. (Neuropathology and Correlative Biology) EORTC 87 NCCTG 34 EORTC Roger Stupp, M.D. (Medical Oncology) Monika Hegi, Ph.D. (Neuropathology and Correlative Biology) NCCTG Study Chair Paul Brown, M.D. Statisticians: Meihua Wang, Ph.D. Minhee Won, M.A. Research Associate: Barbara Kaiser, R.N., C.C.R.P. Sandrine Geinoz, Ph.D., C.C.R.P. Dosimetrist: Protocol Associate: Denise Manfredi, R.T.(T.) Wilma Hoffman, R.N., B.S.N., C.C.R.C., R.A.C. I. Summary: The study opened to accrual on January 17, Through November 4, 2007, 755 patients have been entered. Among 755 registered patients, 746 (99%) patients were eligible for the concurrent radiation and temozolomide stage and 9 (1%) patients were ineligible. Among the 746 eligible patients, the adverse event information for concurrent radiation and temozolomide was available on 491 (66%) patients. Table 2.3 and Table 2.4 present the case status and reason for exclusion. A total of 431 (58%) patients were randomized for adjuvant temozolomide stage and 131 (18%) patients were in pending randomization stage. Table 2.5 and Table 2.6 give the case status relative to randomization and treatment assignment. Of 431 patients randomized, there are 224 (52%) patients with available adverse event information for adjuvant stage. Section III presents the pretreatment characteristics with regard to concurrent radiation and temozolomide stage and adjuvant stage. Section IV presents the adverse events for each treatment stage. There are 491 patients with available adverse events data for the concurrent radiation and temozolomide stage. With respect to adverse events reported as definitely, probably, or possibly related to treatment, 78 (16%), 30 (6%), and 3 (1%) patients experienced grade 3, 4, and 5 respectively (Table 4.1). With respect to adverse events reported as unlikely or unrelated to treatment, 45 (9%), 19 (4%), and 13 (3%) patients experienced grade 3, 4, and 5 respectively (Table 4.3). There are 224 patients with available adverse events data for adjuvant stage. With respect to adverse events reported as definitely, probably, or possibly related to treatment, 19 (19%), 8 (8%), and 3 (3%) patients experienced grade 3, 4, and 5 respectively in Arm 1, while 41 (34%) and 13 (11%) patients experienced grade 3 and 4 respectively in Arm 2 (Table 4.5). With respect to adverse events reported as unlikely or unrelated to treatment, 24 (4%), 4 (4%), and 3 (3%) patients experienced grade 3, 4 and 5 respectively in Arm 1, while 14 (11%), 4 (3%), and 5 (4%) patients experienced grade 3, 4 and 5 respectively in Arm 2 (Table 4.7). II. Administrative Information: Table 2.1 Patient Accrual Study sample size 1,153 Total patients entered through November 4, Average monthly accrual for the study 35.0 Average monthly accrual for the last six months 51.7 Projected completion date based on last six months June 2008

3 January RTOG Full Members and Affiliates (n=505) Table 2.2 Study Accrual THOMAS JEFFERSON UNIV. HOSPITAL 80 THOMAS JEFFERSON UNIV. HOSPITAL 28 TEL-AVIV MEDICAL CENTER 27 AULTMAN HOSPITAL 8 AKRON GENERAL MEDICAL CENTER 6 ABINGTON MEMORIAL HOSPITAL 2 MERCY HOSPITAL 2 UNIV. OF CINCINNATI 2 UNIV. OF IOWA HOSPITALS AND CLINIC 2 PENN STATE UNIV. AND THE MILTON S. 1 PROVIDENCE SAINT JOSEPH MEDICAL CENTER 1 ST. AGNES HEALTHCARE 1 UNIV. OF TEXAS-MD ANDERSON CANCER 42 UNIV. OF TEXAS-MD ANDERSON CANCER 30 BOCA RATON COMMUNITY HOSP.-LYNN REG. 7 MEDICAL COLLEGE OF VIRGINIA HOSPITALS 3 THE MEDICAL CENTER, INC., JOHN B. AMOS 1 UNIV. OF TEXAS MEDICAL BRANCH 1 MEDICAL COLLEGE OF WISCONSIN 32 MEDICAL COLLEGE OF WISCONSIN 12 METHODIST CANCER CENTER 7 GUNDERSON CLINIC 4 INGALLS MEMORIAL HOSPITAL 3 WAUKESHA MEMORIAL HOSPITAL 3 UNITED HOSPITAL SYSTEM 2 THEDACARE CANCER INSTITUTE 1 INTERMOUNTAIN MEDICAL CENTER 26 LDS HOSPITAL 15 INTERMOUNTAIN MEDICAL CENTER 3 UTAH VALLEY REGIONAL MEDICAL CENTER 3 MCKAY-DEE HOSPITAL 2 DIXIE MEDICAL CANCER CENTER 1 MEMORIAL HOSPITAL 1 ST. JOSEPH HOSPITAL COMMUNITY CANCER CE 1 MCGILL UNIV. 22 UNIV. OF WISCONSIN HOSPITAL 22 UNIV. OF WISCONSIN HOSPITAL 18 RAPID CITY REGIONAL HOSPITAL 4 UNIV. OF WESTERN ONTARIO 19 OTTAWA REGIONAL CANCER CENTRE 7 UNIV. OF WESTERN ONTARIO 5 NORTHWESTERN ONTARIO REG. CAN. CENTRE 4 SAINT JOHN REGIONAL HOSPITAL 3 UPMC-SHADYSIDE HOSPITAL 18 UPMC-PRESBYTERIAN HOSPITAL 5 UPMC-ARNOLD PALMER PAVILION 2 UPMC-JAMESON MEMORIAL HOSPITAL 2 UPMC-NATRONA HEIGHTS 2 UPMC-ST. MARGARET 2 UPMC JEFFERSON CANCER CENTER 1 UPMC- PASSAVANT HOSPITAL 1 UPMC-HVHS CANCER CENTER (MOON) 1 UPMC-MCKEESPORT HOSPITAL 1 UPMC-THE WASHINGTON HOSPITAL 1 MAYO CLINIC 17 FLORIDA RADIATION ONCOLOGY GROUP / BAPT 6 JOE ARRINGTON CANCER RESEARCH & TREAT. 5 CENTRACARE HEALTH SYST./COBORN CANCER 2 YAKIMA VALLEY MEMORIAL HOSPITAL 2 MAYO CLINIC 1 SAINT JOHN'S HEALTH SYSTEM CANCER CTR. 1 UNIV. OF CALIFORNIA SAN FRANCISCO 17 YALE CANCER CENTER 5 CITY OF HOPE MEDICAL CENTER 4 ALTA BATES HOSPITAL COMPREHENSIVE CANCE 2 CALIFORNIA PACIFIC MEDICAL CENTER 1 GOOD SAMARITAN HEALTH SYSTEMS 1 POMONA VALLEY HOSPITAL MEDICAL CENTER 1 SALEM HOSPITAL 1 UNIV. OF CALIFORNIA SAN FRANCISCO 1 UNIV. OF WASHINGTON MEDICAL CENTER 1 FOX CHASE CANCER CENTER 16 COMMUNITY MEDICAL CENTER 7 READING HOSPITAL AND MEDICAL CENTER 3 FOX CHASE CANCER CENTER 2 MONMOUTH MEDICAL CENTER 2 THE SCHIFFLER CANCER CENTER 1 VIRTUA-MEM. HOSP. BURLINGTON COUNTY 1 ROSWELL PARK CANCER INSTITUTE 16 ALLEGHENY-SINGER RESEARCH INSTITUTE 7 ANNE ARUNDEL MEDICAL CENTER 6 ROCHESTER GENERAL HOSPITAL 2 ROSWELL PARK CANCER INSTITUTE 1 UNIV. OF UTAH HEALTH SCIENCE CENTE 16 UNIV. OF SOUTH FLORIDA 15 UNIV. OF SOUTH FLORIDA 10 MEDICAL UNIV. OF SOUTH CAROLINA 5 WASHINGTON UNIV. 15 WASHINGTON UNIV. 11 CANCER INSTITUTE OF CAPE GIRARDEAU 2 NORTHWESTERN MEMORIAL HOSPITAL 2 ARIZONA ONCOLOGY SERVICES FOUNDATION 14 DARTMOUTH HITCHCOCK MEDICAL CENTER 14 CONCORD HOSPITAL PAYSON CENTER FOR CAN. 5 DARTMOUTH HITCHCOCK MEDICAL CENTER 5 UNIV. OF VERMONT 3 CHAMPLAIN VALLEY PHYSICIANS HOSPITAL ME 1 L HOTEL-DIEU DE QUEBEC 14 CROSS CANCER INSTITUTE 13 CANCER CARE MANITOBA FOUNDATION 8 ALLAN BLAIR CANCER CENTRE 4 CROSS CANCER INSTITUTE 1 NOTRE DAME HOSPITAL/UNIV. OF MONTR 11

4 January RTOG Full Members and Affiliates (n=505) Table 2.2 Study Accrual (continued) SUNY HEALTH SCIENCE CENTER/BROOKLYN 11 LOYOLA UNIV. MEDICAL CENTER 7 BAPTIST HOSPITAL OF MIAMI 1 MEMORIAL SLOAN KETTERING CANCER CENTER 1 NEW YORK METHODIST HOSPITAL 1 SUNY HEALTH SCIENCE CENTER/BROOKLYN 1 TOM BAKER CANCER CENTRE 9 MCMASTER UNIV., HAMILTON 8 UNIV. OF ROCHESTER 8 UNIV. OF ROCHESTER 6 UNIV. OF OKLAHOMA HEALTH SCIENCES 2 UNIV. OF MARYLAND MEDICAL SYSTEMS 6 UNIV. OF MARYLAND MEDICAL SYSTEMS 4 UNIV. OF CHICAGO 2 MASSACHUSETTS GENERAL HOSPITAL 5 BRIGHAM AND WOMEN'S HOSP./DANA FARBE 2 MASSACHUSETTS GENERAL HOSPITAL 2 CAPE COD HOSPITAL 1 CLEVELAND CLINIC FOUNDATION 4 PRINCESS MARGARET HOSPITAL 4 UNIV. OF TEXAS SOUTHWESTERN MEDICA 3 AKRON CITY HOSPITAL 2 HENRY FORD HOSPITAL 2 RADIOLOGICAL ASSOCIATES OF SACRAMENTO 2 RADIOLOGICAL ASSOCIATES OF SACRAMENTO 1 ROSEVILLE RADIATION ONCOLOGY CENTER 1 UNIV. OF ALABAMA AT BIRMINGHAM MED 2 ST. ALPHONSUS REGIONAL MEDICAL CENTER 2 RTOG CCOP Members and Components (n=129) MICHIGAN CANCER RES, CONSORTIUM CCOP 13 ST. JOSEPH MERCY HOSPITAL 8 SPARROW REGIONAL CANCER CENTER 4 ST. JOHNS HOSPITAL & MEDICAL CENTER 1 COLUMBIA RIVER CCOP 11 BEAUMONT CCOP 10 SOUTHEAST CANCER CONTROL CONSORTIUM, IN 10 MEMORIAL MISSION-ST. JOSEPH'S 6 WAYNE RADIATION ONCOLOGY 2 MEMORIAL MEDICAL CENTER 1 WELLMONT HOLSTON VALLEY MEDICAL CTR. 1 CANCER RESEARCH FOR THE OZARKS 8 COX HEALTH SYSTEM 5 ST. JOHN'S REGIONAL MEDICAL CENTER 3 CHRISTIANA CARE HEALTH SERVICES, INC. 8 COLUMBUS COMM. CLINICAL ONCOLOGY PR 8 METRO-MN CCOP 8 METRO-MN CCOP 6 MERCY HOSPITAL 1 NORTH MEMORIAL MEDICAL CENTER 1 ONCOLOGY HEMATOLOGY ASSOCIATES OF CTR. 6 KANSAS CITY CCOP 5 UPSTATE CAROLINA CCOP 5 WEST MICHIGAN CANCER CENTER CCOP 5 NATALIE WARREN BRYANT CANCER CENTER AT 4 ST. VINCENT REGIONAL CANCER CENTER CCOP 4 VIRGINIA MASON CCOP 4 DAYTON CCOP 3 GOOD SAMARITAN HOSPITAL 1 MIAMI VALLEY HOSPITAL 1 ST. FRANCIS HOSPITAL & HEALTH CENTERS 1 GEISINGER MEDICAL CENTER 3 LIMR/MLH CCOP 3 NEVADA CANCER RESEARCH FOUNDATION 3 UNIV. OF HAWAII CANCER RESEARCH CE 3 NORTHERN INDIANA CANCER RES. CONSORT. 2 GREENVILLE S.C. CCOP 1 GULF COAST MBCCOP 1 ST. LOUIS-CAPE GIRARDEAU CCOP 1

5 January EORTC (n=87) Table 2.2 Study Accrual (continued) RAMBAM MEDICAL CENTER HAIFA 17 BRISTOL ONCOLOGY CENTER 15 NEWCASTLE GENERAL HOSPITAL 14 P. STRADINS CLINICAL UNIV. HOSPITAL 14 CENTRE HOSPITALIER UNIVERSITAIRE VAUDOIS 7 CENTRE HOSPITALIER REG. DE LA CITADEL 5 WESTERN GENERAL HOSPITAL 5 UNIVERSITAETSKLINIKEN BONN 2 AKADEMISCH ZIEKENHUIS VUB 1 ALGEMEEN ZIEKENHUIS SINT LUCAS GENT 1 CAZK GROENINGHE 1 CHRISTIE HOSPITAL 1 HOPITAL DE JOLIMONT 1 WESTON PARK HOSPITAL 1 ADDENBROOKES HOSPITAL 2 NCCTG (n=34) WICHITA CCOP 7 MAYO CLINIC - JACKSONVILLE 5 MISSOURI VALLEY CANCER CCOP/CANCER RESOURCE CENTER SANFORD CANCER CENTER 3 DES MOINES 2 FARGO CCOP 2 GREAT FALLS CLINIC 2 3 MCFARLAND CLINIC 2 ROCHESTER METHODIST HOSPITAL 2 COPLEY MEMORIAL HOSPITAL 1 LEHIGH VALLEY HOSPITAL 1 MERITCARE CLINIC BEMIDJI 1 MISSOURI BAPTIST MEDICAL CENTER 1 NORTH IOWA MERCY CANCER CENTER 1 ST VINCENT'S HEALTH CARE 1

6 January Table 2.3 Case Status for Registered Patients Total patients registered 755 Ineligible 9 Eligible/pending for concurrent RT+TMZ stage 746 With on-study information 744 With adverse event information 491 Table 2.4 Cases Excluded CN Status Reason 5 Ineligible Tumor is not GBM 201 Ineligible Pre-op MRI and post-op CT scan 208 Ineligible Multifocal disease 286 Ineligible Institution error in submitting tissue 298 Ineligible No tissue submission 300 Ineligible No tissue submission 344 Ineligible Tissue was lost in the mail 570 Ineligible Tumor is not GBM 699 Ineligible Tissue was lost in the mail Table 2.5 Case Status Relative to Randomization Total patients randomized (adjuvant TMZ stage) 431 Pending randomization (concurrent RT+TMZ stage) 131 Not randomized post concurrent RT+TMZ stage 184 Insufficient tissue 98 Progression of disease 32 Death 11 Physician preference 10 Patient refusal 7 Other 26 Table 2.6 Case Status for Randomized Patients Arm 1 Arm 2 Total Total patients randomized With on-study information With adverse event information

7 January III. Pretreatment Characteristics: Table 3.1 Pretreatment Characteristics Concurrent Adjuvant TMZ RT+TMZ Stage (n=744) Arm 1 (n=214) Arm 2 (n=217) Age Median Range n % n % n % < Gender Male Female KPS Surgery Biopsy Partial resection Total resection Neurologic Function No symptoms Minor symptoms Moderate symptoms Severe Symptoms 2 < 1 1 < 1 1 < 1 MGMT Status Methylated Unmethylated Unknown (indeterminant, invalid) RPA Class III IV V

8 January Table 3.2 Gender/Ethnicity/Race Distributions Ethnic Category Females Males Total Hispanic or Latino Not Hispanic or Latino Unknown Ethnic Category: Total of All Subjects Racial Category American Indian or Alaskan Native Asian Black or African American White More than one race Unknown Racial Category: Total of All Subjects IV. Adverse Events: Adverse events reported in this section were graded using the CTCAE v 3.0 Criteria. Table 4.1 Adverse Events Concurrent RT + TMZ Stage Reported as Definitely, Probably, or Possibly related to Treatment (n=491) Grade Category Allergy/immunology Auditory/ear Blood/bone marrow Cardiac arrhythmia Cardiac general Constitutional symptoms Death Dermatology/skin Endocrine Gastrointestinal Hemorrhage/bleeding Infection Lymphatics Metabolic/laboratory Musculoskeletal/soft tissue Neurology Ocular/visual Pain Pulmonary/upper respiratory Renal/genitourinary Sexual/reproductive function Syndromes Vascular Worst non-hematologic (23%) (38%) (11%) (1%) (1%) Worst overall (19%) (35%) (16%) (6%) (1%)

9 January Table 4.2 All Grade 3+ Adverse Events from Table 4.1 CN Category Adverse Event Grade 3 Metabolic/Laboratory ALT, SGPT (serum glutamic pyruvic transaminase) 3 4 Blood/Bone Marrow Lymphopenia 3 12 Blood/Bone Marrow Leukocytes (total WBC) 4 Infection Febrile neutropenia (fever of unknown origin without clinically or microbiologically 3 documented infection)(anc<1.0x10e9/l, fever>=38.5º C) 13 Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Platelets 4 25 Constitutional symptoms Fever (in the absence of neutropenia, where neutropenia is defined as 3 ANC<1.0x10e9/L) 31 Gastrointestinal Dehydration 3 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to neuropathy) 3 41 Blood/Bone Marrow Lymphopenia 3 43 Gastrointestinal Anorexia 3 Neurology Neuropathy: motor 3 Pulmonary/Upper respiratory Cough 3 46 Blood/Bone Marrow Neutrophils/granulocytes (ANC/AGC) Metabolic/Laboratory Magnesium, serum-high (hypermagnesemia) 3 57 Blood/Bone Marrow Lymphopenia 3 58 Blood/Bone Marrow Lymphopenia 3 61 Blood/Bone Marrow Platelets 3 Neurology Seizure 3 63 Blood/Bone Marrow Leukocytes (total WBC) 4 68 Blood/Bone Marrow Lymphopenia 3 71 Blood/Bone Marrow Lymphopenia 4 Gastrointestinal Perforation, GI 4 75 Blood/Bone Marrow Platelets 4 Death Death NOS 5 Pulmonary/Upper respiratory Pneumonitis/pulmonary infiltrates 4 87 Metabolic/Laboratory ALT, SGPT (serum glutamic pyruvic transaminase) 3 95 Blood/Bone Marrow Platelets 4 Metabolic/Laboratory ALT, SGPT (serum glutamic pyruvic transaminase) 3 98 Blood/Bone Marrow Platelets Blood/Bone Marrow Platelets Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Platelets 4 Infection Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L) Vascular Thrombosis/embolism (vascular access-related) Neurology Confusion Blood/Bone Marrow Lymphopenia Neurology CNS cerebrovascular ischemia Dermatology/Skin Rash/desquamation Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Platelets 4 Neurology Neuropathy: motor Vascular Thrombosis/thrombus/embolism Neurology Neuropathy: motor 3

10 January Table 4.2 All Grade 3+ Adverse Events from Table 4.1 (continued) CN Category Adverse Event Grade 197 Blood/Bone Marrow Platelets 4 Gastrointestinal Gastrointestinal - Other Blood/Bone Marrow Platelets 4 Gastrointestinal Dehydration Blood/Bone Marrow Platelets Neurology Neuropathy: motor Blood/Bone Marrow Platelets Blood/Bone Marrow Lymphopenia Infection Infection with unknown ANC Blood/Bone Marrow Lymphopenia 3 Metabolic/Laboratory GGT (gamma-glutamyl transpeptidase) Neurology Neuropathy: motor Blood/Bone Marrow Leukocytes (total WBC) Blood/Bone Marrow Platelets 4 Neurology Neuropathy: motor Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Lymphopenia 3 Neurology Neuropathy: motor Blood/Bone Marrow Platelets Blood/Bone Marrow Platelets Blood/Bone Marrow Lymphopenia 4 Infection Infection with normal ANC or Grade 1 or 2 neutrophils Neurology Confusion 4 Ocular/Visual Ophthalmoplegia/diplopia (double vision) Neurology Mood alteration Blood/Bone Marrow Lymphopenia Syndromes Flu-like syndrome Constitutional symptoms Insomnia Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to neuropathy) 3 Neurology Speech impairment (e.g., dysphasia or aphasia) Gastrointestinal Vomiting Blood/Bone Marrow Lymphopenia Musculoskeletal/Soft tissue Musculoskeletal/Soft Tissue - Other Blood/Bone Marrow Neutrophils/granulocytes (ANC/AGC) Blood/Bone Marrow Platelets 3 Infection Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L) 3 Pulmonary/Upper respiratory Pneumonitis/pulmonary infiltrates Blood/Bone Marrow Leukocytes (total WBC) Blood/Bone Marrow Platelets 4 Gastrointestinal Anorexia 3 Metabolic/Laboratory Bilirubin (hyperbilirubinemia) 3 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to neuropathy) Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Platelets Blood/Bone Marrow Lymphopenia Gastrointestinal Vomiting 3 Pulmonary/Upper respiratory Cough 3

11 January Table 4.2 All Grade 3+ Adverse Events from Table 4.1 (continued) CN Category Adverse Event Grade 373 Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Platelets Blood/Bone Marrow Platelets 4 Infection Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L) 5 Metabolic/Laboratory Bilirubin (hyperbilirubinemia) Blood/Bone Marrow Neutrophils/granulocytes (ANC/AGC) 4 Neurology Seizure Metabolic/Laboratory ALT, SGPT (serum glutamic pyruvic transaminase) Metabolic/Laboratory ALT, SGPT (serum glutamic pyruvic transaminase) Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Neutrophils/granulocytes (ANC/AGC) Blood/Bone Marrow Lymphopenia Allergy/Immunology Allergic reaction/hypersensitivity (including drug fever) 3 Cardiac general Hypotension 3 Metabolic/Laboratory Creatinine Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Platelets Blood/Bone Marrow Platelets Gastrointestinal Anorexia Blood/Bone Marrow Platelets Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Leukocytes (total WBC) Blood/Bone Marrow Platelets Blood/Bone Marrow Lymphopenia 3 Pain Headache Blood/Bone Marrow Platelets Blood/Bone Marrow Platelets 4 Metabolic/Laboratory ALT, SGPT (serum glutamic pyruvic transaminase) Blood/Bone Marrow Lymphopenia 3 Gastrointestinal Dysphagia (difficulty swallowing) 3 Neurology Dizziness Neurology Syncope (fainting) Metabolic/Laboratory Glucose, serum-high (hyperglycemia) Blood/Bone Marrow Platelets Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Lymphopenia Constitutional symptoms Insomnia Gastrointestinal Nausea Cardiac general Cardiac General - Other : Cardiopulmonary Arrest 5 Infection Infection - Other: Aspiration Pneumonia 4 Neurology Encephalopathy Blood/Bone Marrow Lymphopenia Blood/Bone Marrow CD4 count Allergy/Immunology Allergic reaction/hypersensitivity (including drug fever) 3 Dermatology/Skin Rash/desquamation 3

12 January Table 4.3 Adverse Events Concurrent RT + TMZ Reported as Unlikely or Unrelated to Treatment (n=491) Grade Allergy/immunology Auditory/ear Blood/bone marrow Cardiac arrhythmia Cardiac general Coagulation Constitutional symptoms Death Dermatology/skin Endocrine Gastrointestinal Hemorrhage/bleeding Hepatobiliary/pancreas Infection Lymphatics Metabolic/laboratory Musculoskeletal/soft tissue Neurology Ocular/visual Pain Pulmonary/upper respiratory Renal/genitourinary Syndromes Vascular Worst non-hematologic (16%) (22%) (9%) (4%) (3%) Worst overall (16%) (22%) (9%) (4%) (3%)

13 January Table 4.4 All Grade 3+ Adverse Events from Table 4.3 CN Category Adverse Event Grade 1 Infection Infection with normal ANC or Grade 1 or 2 neutrophils 3 Metabolic/Laboratory Glucose, serum-high (hyperglycemia) 3 Neurology Cognitive disturbance 3 3 Metabolic/Laboratory Glucose, serum-high (hyperglycemia) 3 4 Blood/Bone Marrow Platelets 4 Death Disease progression NOS 5 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to neuropathy) 3 Neurology Neuropathy: motor 3 Pain Headache 3 Vascular Thrombosis/thrombus/embolism 4 12 Death Death NOS 5 Metabolic/Laboratory Sodium, serum-low (hyponatremia) 3 20 Infection Infection with normal ANC or Grade 1 or 2 neutrophils 3 21 Vascular Thrombosis/thrombus/embolism 3 27 Infection Infection with unknown ANC 3 Neurology Seizure 4 33 Blood/Bone Marrow Lymphopenia 3 41 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to neuropathy) 3 Pain Pain in extremity 3 50 Infection Infection with unknown ANC 5 Metabolic/Laboratory Sodium, serum-low (hyponatremia) 4 57 Neurology Neuropathy: motor 4 71 Endocrine Neuroendocrine: ADH secretion abnormality (e.g., SIADH or low ADH) 3 Metabolic/Laboratory Sodium, serum-low (hyponatremia) 3 Vascular Thrombosis/thrombus/embolism 4 72 Neurology Neuropathy: motor 3 75 Death Death NOS 5 Metabolic/Laboratory Glucose, serum-high (hyperglycemia) 3 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to neuropathy) 3 Neurology Mental status Dermatology/Skin Rash/desquamation Neurology Seizure Metabolic/Laboratory Sodium, serum-low (hyponatremia) Neurology Neuropathy: motor Vascular Thrombosis/thrombus/embolism Death Disease progression NOS 5 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to neuropathy) 3 Neurology Confusion Neurology Memory impairment Vascular Thrombosis/thrombus/embolism Dermatology/Skin Rash/desquamation Neurology Seizure Death Disease progression NOS Neurology Seizure Death Disease progression NOS Dermatology/Skin Rash/desquamation Death Disease progression NOS Metabolic/Laboratory Glucose, serum-high (hyperglycemia) Pulmonary/Upper respiratory Pneumonitis/pulmonary infiltrates 3 Vascular Thrombosis/thrombus/embolism Infection Infection with normal ANC or Grade 1 or 2 neutrophils 3 Metabolic/Laboratory Glucose, serum-high (hyperglycemia) 3 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to neuropathy) Neurology Seizure Gastrointestinal Vomiting 3

14 January CN Category Adverse Event Grade 200 Death Disease progression NOS 5 Neurology Confusion Vascular Thrombosis/thrombus/embolism Metabolic/Laboratory GGT (gamma-glutamyl transpeptidase) Infection Infection - Other Pain Back pain Gastrointestinal Vomiting Constitutional symptoms Insomnia 3 Neurology Pyramidal tract dysfunction (e.g., increased tone, hyperreflexia, positive 3 Babinski, decreased fine motor coordination) Vascular Thrombosis/thrombus/embolism Gastrointestinal Colitis 3 Musculoskeletal/Soft tissue Fracture 3 Vascular Thrombosis/thrombus/embolism Neurology Seizure Neurology Cognitive disturbance Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to neuropathy) 3 Neurology Confusion 3 Vascular Thrombosis/thrombus/embolism Gastrointestinal Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation) 4 Pulmonary/Upper Pulmonary/Upper Respiratory Other: respiratory failure 5 respiratory 264 Dermatology/Skin Pruritus/itching Neurology Syncope (fainting) Allergy/Immunology Allergic reaction/hypersensitivity (including drug fever) 3 Pulmonary/Upper respiratory Hypoxia Neurology Memory impairment Neurology Somnolence/depressed level of consciousness 3 Pain Headache 4 Pulmonary/Upper respiratory Hypoxia Pain Arthralgia Pulmonary/Upper respiratory Pulmonary/Upper Respiratory - Other Metabolic/Laboratory Glucose, serum-high (hyperglycemia) Metabolic/Laboratory Alkalosis (metabolic or respiratory) 4 Neurology Somnolence/depressed level of consciousness Pain Abdominal pain NOS 3 Pulmonary/Upper respiratory Dyspnea (shortness of breath) 3 Vascular Thrombosis/thrombus/embolism Constitutional symptoms Constitutional symptoms - other Neurology Seizure 3 Pulmonary/Upper respiratory Hypoxia 3 Vascular Thrombosis/thrombus/embolism Cardiac general Hypotension 3 Gastrointestinal Dehydration 3 Infection Febrile neutropenia (fever of unknown origin without clinically or 3 microbiologically documented infection)(anc<1.0x10e9/l, fever>= 38.5 degrees C) Renal/Genitourinary Renal failure Neurology CNS cerebrovascular ischemia 3

15 January Table 4.4 All Grade 3+ Adverse Events from Table 4.3 (continued) CN Category Adverse_Event Grade 361 Neurology Pyramidal tract dysfunction (e.g., increased tone, hyperreflexia, 3 positive Babinski, decreased fine motor coordination) 363 Death Death NOS 5 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to 3 neuropathy) Neurology Cognitive disturbance 4 Pulmonary/Upper respiratory Dyspnea (shortness of breath) 3 Renal/Genitourinary Incontinence, urinary Metabolic/Laboratory Potassium, serum-high (hyperkalemia) 4 Neurology CNS cerebrovascular ischemia Vascular Thrombosis/thrombus/embolism Death Disease Progression NOS 5 Gastrointestinal Dysphagia (difficulty swallowing) 3 Infection Infection with normal ANC or Grade 1 or 2 neutrophils 3 Neurology Cognitive disturbance 3 Pulmonary/Upper respiratory Dyspnea (shortness of breath) Gastrointestinal Esophagitis 3 Infection Infection with normal ANC or Grade 1 or 2 neutrophils 3 Metabolic/Laboratory Alkaline phosphatase 3 Neurology Confusion Vascular Thrombosis/thrombus/embolism Infection Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L) Metabolic/Laboratory Glucose, serum-high (hyperglycemia) Infection Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L) 3 Neurology Hydrocephalus Constitutional symptoms Fatigue (asthenia, lethargy, malaise) 4 Vascular Thrombosis/thrombus/embolism Neurology Speech impairment (e.g., dysphasia or aphasia) Infection Infection with normal ANC or Grade 1 or 2 neutrophils 3 Ocular/Visual Optic disc edema 3 Pain Headache Metabolic/Laboratory Glucose, serum-high (hyperglycemia) Metabolic/Laboratory Glucose, serum-high (hyperglycemia) Vascular Thrombosis/thrombus/embolism Neurology Neuropathy: motor 4

16 January Table 4.5 Adverse Events Adjuvant TMZ Reported as Definitely, Probably, or Possibly related to Treatment Arm 1 (n=102) Arm 2 (n=122) Grade Grade Category Auditory/ear Blood/bone marrow Cardiac arrhythmia Cardiac general Constitutional symptoms Death Dermatology/skin Gastrointestinal Hemorrhage/bleeding Infection Lymphatics Metabolic/laboratory Musculoskeletal/soft tissue Neurology Ocular/visual Pain Pulmonary/upper respiratory Renal/genitourinary Vascular Worst non-hematologic (22%) (41%) (8%) (2%) (3%) (20%) (38%) (20%) (1%) Worst overall (14%) (41%) (19%) (8%) (3%) (8%) (31%) (34%) (11%)

17 January Table 4.6 All Grade 3+ Adverse Events from Table 4.5 RX CN Category Adverse Event Grade Arm 1 21 Death Death NOS 5 45 Gastrointestinal Vomiting 3 Neurology Speech impairment (e.g., dysphasia or aphasia) 4 47 Dermatology/Skin Rash/desquamation 3 56 Blood/Bone Marrow Lymphopenia 3 83 Hemorrhage/Bleeding Petechiae/purpura (hemorrhage/bleeding into skin or mucosa) 3 85 Blood/Bone Marrow Lymphopenia 3 92 Blood/Bone Marrow Neutrophils/granulocytes (ANC/AGC) 3 99 Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Lymphopenia 4 Infection Febrile neutropenia (fever of unknown origin without 5 clinically or microbiologically documented infectiona)(anc<1.0x10e9/l, fever>=38.5 degrees C) 161 Blood/Bone Marrow Platelets Blood/Bone Marrow Platelets 4 Musculoskeletal/Soft tissue Musculoskeletal/Soft Tissue - Other 3 Pulmonary/Upper respiratory Pneumonitis/pulmonary infiltrates Blood/Bone Marrow Neutrophils/granulocytes (ANC/AGC) Blood/Bone Marrow Hemoglobin 4 Death Disease progression NOS 5 Pulmonary/Upper respiratory Dyspnea (shortness of breath) Blood/Bone Marrow Platelets Blood/Bone Marrow Platelets Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Leukocytes (total WBC) Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Lymphopenia Metabolic/Laboratory GGT (gamma-glutamyl transpeptidase) Blood/Bone Marrow Neutrophils/granulocytes (ANC/AGC) 4 Gastrointestinal Diarrhea Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Platelets 4 Neurology Confusion Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Platelets Blood/Bone Marrow Leukocytes (total WBC) 4 Neurology CNS cerebrovascular ischemia Neurology Seizure Blood/Bone Marrow Lymphopenia Gastrointestinal Nausea 3 Arm 2 6 Vascular Thrombosis/thrombus/embolism 3 7 Blood/Bone Marrow Lymphopenia 3 13 Metabolic/Laboratory ALT, SGPT (serum glutamic pyruvic transaminase) 3 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to 3 neuropathy) Blood/Bone Marrow Lymphopenia 3 26 Blood/Bone Marrow Lymphopenia 3

18 January Table 4.6 All Grade 3+ Adverse Events from Table 4.5 (continued) RX CN Category Adverse Event Grade Arm 2 33 Blood/Bone Marrow Lymphopenia 3 34 Neurology Neuropathy: motor 3 38 Blood/Bone Marrow Lymphopenia 3 52 Blood/Bone Marrow Lymphopenia 4 62 Blood/Bone Marrow Neutrophils/granulocytes (ANC/AGC) 3 Gastrointestinal Constipation 3 66 Constitutional symptoms Constitutional Symptoms - Other 3 68 Blood/Bone Marrow Lymphopenia 4 78 Neurology Seizure 3 79 Blood/Bone Marrow Lymphopenia 4 89 Blood/Bone Marrow Lymphopenia 3 Pain Arthralgia 3 93 Blood/Bone Marrow Lymphopenia 4 Constitutional symptoms Weight loss 3 96 Blood/Bone Marrow Lymphopenia 4 Infection Opportunistic infection associated with >=Grade 2 Lymphopenia Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Lymphopenia 4 Vascular Thrombosis/embolism (vascular access-related) Blood/Bone Marrow Platelets Gastrointestinal Dehydration 3 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to 3 neuropathy) Neurology Ataxia (incoordination) Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Lymphopenia Gastrointestinal Anorexia 3 Infection Opportunistic infection associated with >=Grade 2 Lymphopenia 3 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to 4 neuropathy) 192 Blood/Bone Marrow Lymphopenia 3 Gastrointestinal Nausea Blood/Bone Marrow Platelets Blood/Bone Marrow Platelets 3 Metabolic/Laboratory ALT, SGPT (serum glutamic pyruvic transaminase) Blood/Bone Marrow Lymphopenia Pain Headache Blood/Bone Marrow CD4 count Blood/Bone Marrow Neutrophils/granulocytes (ANC/AGC) Blood/Bone Marrow CD4 count Blood/Bone Marrow Lymphopenia 3 Gastrointestinal Nausea Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Neutrophils/granulocytes (ANC/AGC) Blood/Bone Marrow Lymphopenia Blood/Bone Marrow CD4 count Blood/Bone Marrow Lymphopenia 3

19 January Table 4.6 All Grade 3+ Adverse Events from Table 4.5 (continued) RX CN Category Adverse_Event Grade Arm Gastrointestinal Anorexia Blood/Bone Marrow CD4 count 3 Neurology Seizure Blood/Bone Marrow Lymphopenia Gastrointestinal Nausea Blood/Bone Marrow Lymphopenia Blood/Bone Marrow Lymphopenia Blood/Bone Marrow CD4 count Blood/Bone Marrow Lymphopenia Gastrointestinal Anorexia Blood/Bone Marrow Lymphopenia 3 Table 4.7 Adverse Events Adjurant TMZ Reported as Unlikely or Unrelated to Treatment Arm 1 Arm 2 (n=102) (n=122) Grade Grade Category Allergy/immunology Auditory/ear Blood/bone marrow Cardiac arrhythmia Cardiac general Coagulation Constitutional symptoms Death Dermatology/skin Endocrine Gastrointestinal Hemorrhage/bleeding Hepatobiliary/pancreas Infection Lymphatics Metabolic/laboratory Musculoskeletal/soft tissue Neurology Ocular/visual Pain Pulmonary/upper respiratory Renal/genitourinary Sexual/reproductive function Vascular Worst non-hematologic (12%) (25%) (23%) (3%) (3%) (16%) (34%) (11%) (2%) (4%) Worst overall (12%) (24%) (24%) (4%) (3%) (16%) (34%) (11%) (3%) (4%)

20 January Table 4.8 All Grade 3+ Adverse Events from Table 4.7 RX CN Category Adverse Event Grade Arm 1 1 Blood/Bone Marrow Neutrophils/granulocytes (ANC/AGC) 3 Infection Infection with unknown ANC 3 3 Metabolic/Laboratory Glucose, serum-high (hyperglycemia) 3 10 Death Disease progression NOS 5 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to neuropathy) 3 Neurology Mood alteration 4 11 Blood/Bone Marrow Platelets 3 Metabolic/Laboratory Glucose, serum-high (hyperglycemia) 3 16 Endocrine Neuroendocrine: gonadotropin secretion abnormality 3 Metabolic/Laboratory Glucose, serum-high (hyperglycemia) 3 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to neuropathy) 3 41 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to neuropathy) 3 46 Vascular Thrombosis/thrombus/embolism 3 47 Dermatology/Skin Pruritus/itching 3 Neurology Seizure 3 58 Blood/Bone Marrow Lymphopenia 3 72 Death Disease progression NOS 5 Neurology Neuropathy: motor Neurology Seizure Vascular Thrombosis/thrombus/embolism Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to neuropathy) Neurology Speech impairment (e.g., dysphasia or aphasia) Constitutional symptoms Weight gain 3 DEATH Disease progression NOS 5 Metabolic/Laboratory Phosphate, serum-low (hypophosphatemia) 3 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to neuropathy) 3 Neurology Somnolence/depressed level of consciousness 3 Pain Headache Neurology Memory impairment Metabolic/Laboratory Sodium, serum-low (hyponatremia) Neurology Seizure Neurology Neuropathy: motor Cardiac general Cardiac troponin I (ctni) 4 Infection Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L) 4 Pulmonary/Upper respiratory Pneumonitis/pulmonary infiltrates Neurology Neuropathy: motor Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to neuropathy) Neurology Neurology - Other Pulmonary/Upper respiratory Pneumonitis/pulmonary infiltrates Blood/Bone Marrow Platelets 4 Neurology Hydrocephalus Neurology Seizure Blood/Bone Marrow Hemoglobin Neurology Neuropathy: motor Metabolic/Laboratory Sodium, serum-low (hyponatremia) 3 Neurology Neuropathy: motor 3 Vascular Thrombosis/thrombus/embolism Hepatobiliary/Pancreas Cholecystitis Metabolic/Laboratory ALT, SGPT (serum glutamic pyruvic transaminase) 3

21 January Table 4.8 All Grade 3+ Adverse Events from Table 4.7 (continued) RX CN Category Adverse Event Grade Arm 2 13 Death Death not associated with CTCAE term 5 22 Neurology Syncope (fainting) 3 34 Neurology Seizure 3 39 Lymphatics Lymphatics - Other 3 Neurology Neuropathy: motor 3 52 Blood/Bone Marrow Lymphopenia 4 78 Vascular Thrombosis/thrombus/embolism 4 96 Neurology CNS necrosis/cystic progression 4 Pulmonary/Upper respiratory Hypoxia 3 Vascular Thrombosis/thrombus/embolism 3 97 Neurology Neuropathy: motor Neurology Memory impairment Death Death not associated with CTCAE term 5 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area (not due to neuropathy) Blood/Bone Marrow Hemoglobin 3 Neurology Ataxia (incoordination) 3 Pain Abdominal pain NOS Pulmonary/Upper respiratory Aspiration Gastrointestinal Dehydration Coagulation INR (International Normalized Ratio of prothrombin time) Death Death not associated with CTCAE term 5 Gastrointestinal Dysphagia (difficulty swallowing) 3 Neurology Cognitive disturbance Death Death not associated with CTCAE term Neurology Confusion Infection Febrile neutropenia (fever of unknown origin without clinicallay or 3 microbiologically documented infection)(anc<1.0x10e9/l, fever>=38.5 degrees C) 264 Infection Infection with normal ANC or Grade 1 or 2 neutrophils Pain Headache Neurology Tremor Infection Infection with unknown ANC Infection Infection with normal ANC or Grade 1 or 2 neutrophils 3