June Opened: January 17, 2006 Closed: June 13, 2008

Transcription

1 June RTOG Protocol No: 0525 Protocol Status: Opened: January 17, 2006 Closed: June 13, 2008 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. Indeterminate 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 June Study Chairs: Medical Oncology Total patients entered: 1173 Mark R. Gilber, M.D. (Principal Investigator) RTOG RTOG 918 Roger Stupp, M.D. EORTC EORTC 188 Kurt A. Jaeckle, M.D. NCCTG NCCTG 67 Radiation Oncology Minesh Mehta, M.D. Paul Brown, M.D. Neuropathology & Correlative Biology Ken Aldape, M.D. Arnab Chakravarti, M.D. Monika Hegi, Ph.D. Quality of Life Terri Armstrong, Ph.D. RTOG NCCTG RTOG RTOG EORTC RTOG 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: The study opened to accrual on January 17, 2006, and closed to accrual on June 13, 2008, with 1173 patients entered. Among registered patients, 1150 (98%) were eligible for the concurrent radiation and temozolomide stage and 23 (2%) were ineligible. Table 2.3 and Table 2.4 present the case status and reason for exclusion. A total of 834 (73%) patients were randomized for the adjuvant temozolomide stage. Table 2.5 and Table 2.6 give the case status relative to randomization and treatment assignment. Of 834 patients randomized, there are 697 (84%) patients with available adverse event (AE) information for the adjuvant stage. Section III presents the pretreatment characteristics with regard to the concurrent radiation and temozolomide stage and the adjuvant stage. Adverse events are scored by CTCAE version 3.0. The numbers in AEs category frequency tables in Section IV represent the number of patients who experienced that grade AE for a particular category; patients are only counted once for each category using their highest grade experienced. In the listings of AE terms, all AEs of a specified grade or higher are listed by category and term. For example, if a patient experienced grade 3 dehydration and grade 4 diarrhea, both of which are in the GI category, this patient would be represented in the grade 4 column of the category main table; however, in the listing of AE terms, both the grade 3 dehydration and grade 4 diarrhea would be listed for this patient (if the listing was for grade 3 or higher). There are 1120 patients with available AEs data for the concurrent radiation and temozolomide stage. With respect to AEs reported as definitely, probably, or possibly related to treatment, 215 (19%), 95 (8%), and 4 (<1%) patients experienced grade 3, 4, and 5 (fatal ) events, respectively (Table 4.1). With respect to AEs reported regardless of relationship to treatment, 267 (24%), 130 (12%), and 30 (3%) patients experienced grade 3, 4, and 5 events, respectively (Table 4.3). There are 697 patients with available AE data for the adjuvant stage. With respect to AEs reported as definitely, probably, or possibly related to treatment, 77 (23%), 32 (10%), and 2 (1%) patients experienced grade 3, 4, and 5 (fatal) events, respectively, in Arm 1; 135 (37%), 42 (12%), and 4 (1%) patients experienced grade 3, 4 and 5 ( fatal ) events, respectively, in Arm 2 (Table 4.4). With respect to AEs reported regardless of relationship to treatment, 115 (34%), 50 (15%), and 8 (2%) patients experienced grade 3, 4 and 5 events, respectively, in Arm 1; 148 (41%), 62 (17%), and 15 (4%) patients experienced grade 3, 4 and 5 events, respectively, in Arm 2 (Table 4.6). Radiotherapy and chemotherapy review results are shown in Tables 5.1 and 5.2. Twenty percent of patients were randomly selected in RTOG/NCCTG for radiotherapy review and completed. Radiotherapy reviews on 34 randomly selected patients from EORTC are also complete. At this time, 20 (6%) chemotherapy reviews for the not-randomized patients have been completed; for the randomized arms, 26 (6%) and 29 (7%) of chemotherapy reviews have been completed for Arm 1 and Arm 2, respectively.

3 June II. Administrative Information: Table 2.1 Patient Accrual Study sample size 1153 Total patients entered 1173 Average monthly accrual for the study 40.7 RTOG Full Members and Affiliates (n=737) THOMAS JEFFERSON UNIV. HOSPITAL 118 TEL-AVIV MEDICAL CENTER 45 THOMAS JEFFERSON UNIV. HOSPITAL 37 AULTMAN HOSPITAL 8 AKRON GENERAL MEDICAL CENTER 7 PENN STATE UNIV. AND THE MILTON S. HERSHEY 4 MEDICAL CTR ABINGTON MEMORIAL HOSPITAL 3 ST. AGNES HEALTHCARE 3 NEVADA CANCER INSTITUTE 2 UNIV. OF CINCINNATI 2 UNIV. OF IOWA HOSPITALS AND CLINICS 2 USON-WILLIAMETTE VALLEY CANCER CENTER 2 PROVIDENCE SAINT JOSEPH MEDICAL CENTER 1 RADIATION ONCOLOGY ASSOCIATES 1 SAINT BARNABAS MEDICAL CENTER 1 UNIV. OF TEXAS-MD ANDERSON CANCER 61 UNIV. OF TEXAS-MD ANDERSON CANCER CTR. 37 BOCA RATON COMMUNITY HOSPITAL-LYNN 9 REGIONAL CANCER CENTER MEDICAL COLLEGE OF VIRGINIA HOSPITALS 5 UNIV. OF FLORIDA COLLEGE OF MEDICINE 4 THOMPSON CANCER SURVIVAL CENTER 3 THE MEDICAL CENTER, INC., JOHN B. AMOS 2 CANCER CENTER UNIV. OF TEXAS MEDICAL BRANCH 1 MEDICAL COLLEGE OF WISCONSIN 37 MEDICAL COLLEGE OF WISCONSIN 13 METHODIST CANCER CENTER 11 GUNDERSON CLINIC 4 INGALLS MEMORIAL HOSPITAL 3 WAUKESHA MEMORIAL HOSPITAL 3 COMMUNITY MEMORIAL HOSPITAL 1 THEDACARE CANCER INSTITUTE 1 UNITED HOSPITAL SYSTEM 1 INTERMOUNTAIN MEDICAL CENTER 32 LDS HOSPITAL 15 INTERMOUNTAIN MEDICAL CENTER 5 UTAH VALLEY REGIONAL MEDICAL CENTER 4 DIXIE MEDICAL CANCER CENTER 2 MCKAY-DEE HOSPITAL 2 ST. JOSEPH HOSPITAL COMM. CANCER CENTER 2 MEMORIAL HOSPITAL 1 PENROSE CANCER CENTER, PENROSE-ST. FRANCIS 1 HEALTH SERVICES Table 2.2 Study Accrual MCGILL UNIV. 29 UNIV. OF CALIFORNIA SAN FRANCISCO 29 UNIV. OF WASHINGTON MEDICAL CENTER 9 YALE CANCER CENTER 7 CITY OF HOPE MEDICAL CENTER 5 ALTA BATES HOSPITAL COMPREHENSIVE 2 CANCER CENTER GOOD SAMARITAN HEALTH SYSTEMS 2 CALIFORNIA PACIFIC MEDICAL CENTER 1 POMONA VALLEY HOSPITAL MEDICAL CENTER 1 SALEM HOSPITAL 1 UNIV. OF CALIFORNIA SAN FRANCISCO 1 ARIZONA ONCOLOGY SERVICES FOUNDATION 26 ARIZONA ONCOLOGY SERVICES FOUNDATION 22 THE UNIV. OF ARIZONA 4 ROSWELL PARK CANCER INSTITUTE 25 ALLEGHENY-SINGER RESEARCH INSTITUTE 11 ANNE ARUNDEL MEDICAL CENTER 7 ROCHESTER GENERAL HOSPITAL 4 ROSWELL PARK CANCER INSTITUTE 3 UNIV. OF WISCONSIN HOSPITAL 25 UNIV. OF WISCONSIN HOSPITAL 20 RAPID CITY REGIONAL HOSPITAL 4 UNIV. OF WISCONSIN CANCER C JOHNSON CREEK 1 H. LEE MOFFITT CANCER CENTER & RESEARCH 24 H. LEE MOFFITT CANCER CENTER & RES. INST. 16 MEDICAL UNIV. OF SOUTH CAROLINA 7 MOFFITT SOUTH CANCER CENTER 1 SUNY HEALTH SCIENCE CENTER/BROOKLYN 24 LOYOLA UNIV. MEDICAL CENTER 10 MEMORIAL SLOAN KETTERING CANCER CTR. 8 BAPTIST HOSPITAL OF MIAMI 2 NEW YORK METHODIST HOSPITAL 2 KAISER PERMANENTE LOS ANGELES MED. CTR. 1 SUNY HEALTH SCIENCE CENTER/BROOKLYN 1 UNIV. OF WESTERN ONTARIO 24 THE OTTAWA HOSPITAL REGIONAL CANCER 10 CENTRE UNIV. OF WESTERN ONTARIO 6 NORTHWESTERN ONTARIO REGIONAL CANCER 4 CENTRE SAINT JOHN REGIONAL HOSPITAL 4

4 June RTOG Full Members and Affiliates (n=737) Table 2.2 Study Accrual UPMC-SHADYSIDE HOSPITAL 24 UPMC-PRESBYTERIAN HOSPITAL 5 MERCY HOSPITAL 3 UPMC-ST. MARGARET 3 UPMC- PASSAVANT HOSPITAL 2 UPMC-ARNOLD PALMER PAVILION 2 UPMC-JAMESON MEMORIAL HOSPITAL 2 UPMC-MCKEESPORT HOSPITAL 2 UPMC-NATRONA HEIGHTS 2 UPMC JEFFERSON CANCER CENTER 1 UPMC-HVHS CANCER CENTER (MOON) 1 UPMC-THE WASHINGTON HOSPITAL 1 MAYO CLINIC 23 FLORIDA RADIATION ONCOLOGY GROUP / 7 BAPTIST REGIONAL JOE ARRINGTON CANCER RESEARCH & 7 TREATMENT CENTER CENTRACARE HEALTH SYSTEM/COBORN CANCER 2 CENTER YAKIMA VALLEY MEMORIAL HOSPITAL 2 ICON- FLORIDA CANCER CENTER-BEACHES 1 MAYO CLINIC 1 MAYO RADIATION ONCOLOGY CENTER 1 POUDRE VALLEY RADIATION ONCOLOGY 1 SAINT JOHN'S HEALTH SYSTEM CANCER CTR. 1 WASHINGTON UNIV. 23 WASHINGTON UNIV. 17 CANCER INSTITUTE OF CAPE GIRARDEAU 2 METHODIST MEDICAL CENTER OF ILLINOIS 2 NORTHWESTERN MEMORIAL HOSPITAL 2 MASSACHUSETTS GENERAL HOSPITAL 22 MASSACHUSETTS GENERAL HOSPITAL 12 CONCORD HOSPITAL PAYSON CENTER FOR 5 CANCER CARE BRIGHAM AND WOMEN'S HOSPITAL/DANA 2 FARBER CANCER INSTITUTE CAPE COD HOSPITAL 2 THE METHODIST HOSPITAL 1 UNIV. OF UTAH HEALTH SCIENCE CENTE 20 FOX CHASE CANCER CENTER 19 COMMUNITY MEDICAL CENTER 7 READING HOSPITAL AND MEDICAL CENTER 5 FOX CHASE CANCER CENTER 3 MONMOUTH MEDICAL CENTER 2 THE SCHIFFLER CANCER CENTER 1 VIRTUA-MEMORIAL HOSPITAL BURLINGTON 1 COUNTY, INC. L HOTEL-DIEU DE QUEBEC 16 MCMASTER UNIV, JURAVINSKI CAN CTR, HAMI 16 NOTRE DAME HOSPITAL/UNIV. OF MONTR 16 CROSS CANCER INSTITUTE 15 CANCER CARE MANITOBA FOUNDATION 9 ALLAN BLAIR CANCER CENTRE 5 CROSS CANCER INSTITUTE 1 CLEVELAND CLINIC FOUNDATION 14 CLEVELAND CLINIC FOUNDATION 13 SENTARA NORFOLK GENERAL HOSPITAL 1 DARTMOUTH HITCHCOCK MEDICAL CENTER 13 DARTMOUTH HITCHCOCK MEDICAL CENTER 8 UNIV. OF VERMONT 4 CHAMPLAIN VALLEY PHYSICIANS HOSPITAL 1 MEDICAL CENTER UNIV. OF ROCHESTER 11 UNIV. OF ROCHESTER 7 UNIV. OF OKLAHOMA HEALTH SCIENCES CENTER 4 TOM BAKER CANCER CENTRE 9 UNIV. OF ALABAMA AT BIRMINGHAM MED 7 ST. ALPHONSUS REGIONAL MEDICAL CENTER 4 PIEDMONT HOSPITAL 3 UNIV. OF MARYLAND MEDICAL SYSTEMS 7 UNIV. OF MARYLAND MEDICAL SYSTEMS 5 UNIV. OF CHICAGO 2 UNIV. OF TEXAS SOUTHWESTERN MEDICA 7 HENRY FORD HOSPITAL 5 PRINCESS MARGARET HOSPITAL 4 UNIV. OF MICHIGAN MEDICAL CENTER 4 PROVIDENCE HOSPITAL 4 AKRON CITY HOSPITAL 3 AKRON CITY HOSPITAL 2 CANCER TREATMENT CENTER 1 RADIOLOGICAL ASSOCIATES OF SACRAMENTO 3 NORTHRIDGE HOSPITAL MEDICAL CENTER 1 RADIOLOGICAL ASSOCIATES OF SACRAMENTO 1 ROSEVILLE RADIATION ONCOLOGY CENTER 1 WAYNE STATE UNIV.-KARMANOS CANCER 2 NORTHWEST COMMUNITY HOSPITAL 2

5 June RTOG CCOP Members and Components (n=181) Table 2.2 Study Accrual MICHIGAN CANCER RES, CONSORTIUM CCO ST. JOSEPH MERCY HOSPITAL SPARROW REGIONAL CANCER CENTER 7 GENESYS REGIONAL MEDICAL CENTER ST. JOHNS HOSPITAL & MEDICAL CENTER 1 1 COLUMBIA RIVER CCOP 16 SOUTHEAST CANCER CONTROL CONSORT., IN 13 MEMORIAL MISSION-ST. JOSEPH'S WAYNE RADIATION ONCOLOGY 8 2 WELLMONT HOLSTON VALLEY MED. CTR. 2 MEMORIAL MEDICAL CENTER 1 BEAUMONT CCOP 12 CHRISTIANA CARE HEALTH SERVICES, INC. 12 CANCER RESEARCH FOR THE OZARKS COX HEALTH SYSTEM 11 7 ST. JOHN'S REGIONAL MEDICAL CENTER 3 ST. JOHN'S REGIONAL HEALTH SYSTEM 1 METRO-MN CCOP 10 METRO-MN CCOP MERCY HOSPITAL 8 1 NORTH MEMORIAL MEDICAL CENTER 1 ILLINOIS CANCERCARE 9 COLUMBUS COMMUNITY CLINICAL ONC, PR 8 WEST MICHIGAN CANCER CENTER CCOP 7 GEISINGER MEDICAL CENTER 6 KANSAS CITY CCOP 6 NATALIE WARREN BRYANT CANCER CTR. AT 5 NEVADA CANCER RESEARCH FOUNDATION 5 UPSTATE CAROLINA CCOP 5 VIRGINIA MASON CCOP 5 DAYTON CCOP 4 MIAMI VALLEY HOSPITAL GOOD SAMARITAN HOSPITAL 2 1 ST. FRANCIS HOSPITAL & HEALTH CENTERS 1 NORTHERN INDIANA CANCER RES. CONSOR 4 LIMR/MLH CCOP LIMR/MLH CCOP 3 2 PAOLI MEMORIAL HOSPITAL 1 UNIV. OF HAWAII CANCER RESEARCH CE 3 JOHN H. STROGER, JR., HOSPITAL OF COOK 2 MONTANA CANCER CONSORTIUM CCOP 2 BENEFIS HEALTHCARE-SLETTEN CANCER INSTITUTE 2 NORTH SHORE UNIV. HOSPITAL CCOP 2 TOLEDO COMMUNITY HOSP. ONCOL. PROG 2 FLOWER HOSPITAL 2 GREENVILLE S.C. CCOP 1 GULF COAST MBCCOP 1 ST. LOUIS-CAPE GIRARDEAU CCOP 1 ST. VINCENT REGIONAL CANCER CTR. CCOP 6

6 June EORTC (n=188) Table 2.2 Study Accrual P. STRADINS CLINICAL UNIV. HOSPITAL 29 BRISTOL ONCOLOGY CENTER 27 RAMBAM MEDICAL CENTER HAIFA 26 NEWCASTLE GENERAL HOSPITAL 18 CHRISTIE HOSPITAL 11 WESTERN GENERAL HOSPITAL 11 CENTRE HOSPITALIER REGIONAL DE LA CITADEL 7 CENTRE HOSPITALIER UNIVERSITAIRE VAUDOIS 7 CLINIQUEST UNIVERSITAIRES ST. LUC 7 DR. BERNANRD VERBEETEN INSTITUUT 6 UNIVERSITAETSKLINIKEN BONN 6 ADDENBROOKES HOSPITAL 5 MEDISCH CENTRUM HAAGLANDNE-WESTEINDE 4 WESTON PARK HOSPITAL 4 C.H.U. DE LA TIMONE 3 CENTRE EUGENE MARQUIS RENNES 3 CENTRE F. LECLERC 3 ERASMUS UNIV. MEDICAL CENTER 3 AKADEMISCH ZIEKENHUIS VUB 2 HOPITAL DE JOLIMONT 2 ALGEMEEN ZIEKENHUIS SINT LUCAS GENT 1 CAZK GROENINGHE 1 ROYAL SUSSEX COUNTY HOSPITAL 1 UZ GASTHUISBERG LEUVEN 1 NCCTG (n=67) WICHITA CCOP 14 MAYO CLINIC - JACKSONVILLE 8 ROCHESTER METHODIST HOSPITAL 8 SANFORD CANCER CENTER 5 DES MOINES 4 FARGO CCOP 4 MCFARLAND CLINIC 3 MISSOURI VALLEY CANCER CCOP/CANCER RESOURCE CENTER CARLE CLINIC ASSOCIATION 2 GREAT FALLS CLINIC 2 IMMANUEL MEDICAL CENTER 2 3 LEHIGH VALLEY HOSPITAL 2 BILLINGS DEACONESS HOSPITAL 1 CEDAR RAPIDS 1 COPLEY MEMORIAL HOSPITAL 1 MAYO CLINIC SCOTTSDALE 1 MEMORIAL REGIONAL CANCER CENTER 1 MERITCARE CLINIC BEMIDJI 1 MISSOURI BAPTIST MEDICAL CENTER 1 NORTH IOWA MERCY CANCER CENTER 1 SMDC HEALTH SYSTES - DULUTH CLINIC 1 ST VINCENT'S HEALTH CARE 1

7 June Table 2.3 Case Status for Registered Patients Total Total patients entered 1173 Ineligible 23 Eligible/pending 1150 With on-study information 1150 With adverse event information 1120 No protocol treatment 23 Table 2.4 Cases Excluded (n=23) Reason n % Ineligible - Tumor is not GBM/Gliosarcoma 6 26 Ineligible - No tissue submission 5 22 Ineligible - Multifocal disease 3 13 Ineligible - IMRT used 2 9 Ineligible Ineligible lab values 2 9 Ineligible - Pre-op MRI and post-op CT scan 2 9 Ineligible - Institution error in submitting tissue 1 4 Ineligible - No pre-op scan 1 4 Ineligible - Tissue was lost in the mail 1 4 Table 2.5 Case Status Relative to Randomization Total patients randomized (adjuvant TMZ stage) 834 Not randomized post concurrent RT+TMZ stage 316 Insufficient tissue 137 Progression of disease 54 Death 21 Patient refusal 21 Physician preference 18 Toxicity 8 Other complicating disease 2 Other 40 Pending (No A2 form received) 15 Table 2.6 Case Status for Randomized Patients Arm 1 Arm 2 Total Total patients randomized With on-study information With adverse event information

8 June III. Pretreatment Characteristics: Table 3.1 Pretreatment Characteristics Concurrent Adjuvant TMZ RT+TMZ Stage (n= 1150) Arm 1 (n=412) Arm 2 (n=422) 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 <1 4 1 MGMT Status Methylated Unmethylated Unknown (indeterminate, invalid) RPA Class III IV V

9 June Table 3.2 Gender/Ethnicity/Race Distributions Sex/Gender Ethnic Category Females Males Total Hispanic or Latino Not Hispanic or Latino Unknown (Individuals not reporting ethnicity) Ethnic Category: Total of All Subjects Racial Category American Indian/Alaska Native Asian Black or African American More than one race Native Hawaiian or Other Pacific Islander Unknown or not reported White Racial Category: Total of All Subjects Table 3.3 Pretreatment QOL Compliance* (n=249) n % HVLT Completed Trail not tested 8 3 Trail discontinued 1 <1 Not done 2 1 Not received COWA Completed Trail not tested 7 3 Trail discontinued 5 2 Not done 5 2 Not received Trail A Completed Trail not tested 8 3 Trail discontinued 2 1 Not done 1 <1 Not received Trail B Completed Trail not tested 8 3 Trail discontinued 11 4 Not done 1 <1 Not received EORTC QLQ-C30 Completed Not done 11 4 Not received M.D. Anderson Symptom Inventory Completed Not done 11 4 Not received *QOL component was added per amendment #2 (broadcast on 7/12/2007).

10 June 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=1120) Grade Category Allergy/immunology Auditory/ear Blood/bone marrow Cardiac Arrhythmia Cardiac general Coagulation Constitutional symptoms Dermatology/skin Endocrine Gastrointestinal Hemorrhage/bleeding Hepatobiliary/pancreas Infection Lymphatics Metabolic/laboratory Musculoskeletal/soft tissue Neurology Ocular/visual Pain Pending Pulmonary/upper respiratory Renal/genitourinary Sexual/reproductive function Syndromes Vascular Worst non-hematologic (21%) (35%) (15%) (3%) (<1%) Worst overall (17%) (31%) (19%) (8%) (<1%) * Includes adverse events where relationship to treatment is missing

11 June Table 4.2 All Grade 3+ Adverse Events from Table 4.1 CN Category Adverse Event Grade 3 Metabolic/laboratory Alanine aminotransferase increased 3 4 Blood/bone marrow 9 Vascular Thrombosis 3 12 Blood/bone marrow Leukopenia NOS 4 Infection Febrile neutropenia 3 13 Blood/bone marrow 17 Pending Pending 3 21 Blood/bone marrow 24 Blood/bone marrow Neurology Cerebral ischaemia 4 25 Constitutional symptoms Pyrexia 3 28 Pulmonary/upper respiratory Dyspnoea 3 Vascular Thrombosis 3 31 Gastrointestinal Dehydration 3 Nausea 3 Vomiting NOS 3 Musculoskeletal/soft tissue Muscle weakness NOS 3 41 Blood/bone marrow Metabolic/laboratory Blood alkaline phosphatase increased 3 43 Gastrointestinal Anorexia 3 Nausea 3 Vomiting NOS 3 Neurology Peripheral motor neuropathy 3 Pending Pending 3 Pulmonary/upper respiratory Cough 3 45 Metabolic/laboratory Hyponatremia 3 46 Blood/bone marrow Blood/bone marrow Leukopenia NOS 4 Metabolic/laboratory Hypermagnesaemia 3 51 Infection Infection with normal ANC or Grade 1 or 2 neutrophils: 3 Wound 57 Blood/bone marrow 58 Blood/bone marrow 59 Pending Pending 3 61 Blood/bone marrow Neurology Convulsions NOS 3 63 Blood/bone marrow Leukopenia NOS 4 68 Blood/bone marrow 71 Blood/bone marrow Gastrointestinal Colonic perforation 4 Small intestinal stricture NOS 3 75 Blood/bone marrow Leukopenia NOS 3 Pulmonary/upper respiratory Pneumonitis NOS 4

12 June Table 4.2 All Grade 3+ Adverse Events from Table 4.1 CN Category Adverse Event Grade 76 Neurology Syncope 3 78 Metabolic/laboratory Alanine aminotransferase increased 3 87 Metabolic/laboratory Alanine aminotransferase increased 3 95 Blood/bone marrow Hemoglobin 4 Metabolic/laboratory Alanine aminotransferase increased 3 98 Blood/bone marrow Leukopenia NOS Blood/bone marrow 106 Blood/bone marrow CD4 lymphocytes decreased Blood/bone marrow 111 Blood/bone marrow 112 Infection Skin infection Blood/bone marrow Pending Pending Blood/bone marrow 136 Blood/bone marrow Bone marrow depression NOS 3 Hemoglobin 3 Leukopenia NOS 4 Infection Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 3 10e9/L): Rectum 137 Vascular Vascular access NOS complication Neurology Confusional state 3 Memory impairment Blood/bone marrow 145 Metabolic/laboratory Alanine aminotransferase increased 4 Aspartate aminotransferase increased Blood/bone marrow Metabolic/laboratory Hypokalemia Blood/bone marrow 154 Neurology Cerebral ischaemia Dermatology/skin Dermatitis exfoliative NOS Blood/bone marrow Blood/bone marrow 188 Blood/bone marrow 189 Blood/bone marrow Neurology Depressed level of consciousness 3 Peripheral motor neuropathy 3 Pending Pending Vascular Thrombosis Neurology Peripheral motor neuropathy Blood/bone marrow Pending Pending Blood/bone marrow Haemolysis NOS 3 Leukopenia NOS 4 Gastrointestinal Dehydration 3

13 June Table 4.2 All Grade 3+ Adverse Events from Table 4.1 CN Category Adverse Event Grade 200 Blood/bone marrow 206 Blood/bone marrow Metabolic/laboratory Alanine aminotransferase increased 4 Aspartate aminotransferase increased 3 Blood alkaline phosphatase increased 3 Blood bilirubin increased 3 Lipase increased Blood/bone marrow 217 Blood/bone marrow 218 Blood/bone marrow 224 Infection Infection with unknown ANC: Meninges (meningitis) Blood/bone marrow Metabolic/laboratory Gamma-glutamyltransferase increased Neurology Peripheral motor neuropathy Blood/bone marrow Leukopenia NOS 3 Infection Infection - Other: Blood/bone marrow Neurology Ataxia 3 Peripheral motor neuropathy Blood/bone marrow 235 Gastrointestinal Colitis NOS Blood/bone marrow 245 Neurology Convulsions NOS Blood/bone marrow 256 Constitutional symptoms Fatigue 4 Pain Myalgia 3 Vascular Thrombosis Blood/bone marrow Neurology Peripheral motor neuropathy Blood/bone marrow Blood/bone marrow Leukopenia NOS Infection Infection - Other: Blood/bone marrow Infection Pneumonia NOS 4 Sinusitis NOS Neurology Confusional state 4 Convulsions NOS 3 Ocular/visual Diplopia Metabolic/laboratory Gamma-glutamyltransferase increased 3 Musculoskeletal/soft tissue Gait abnormal NOS 3 Neurology Convulsions NOS 3 Vascular Vascular access NOS complication 3

14 June Table 4.2 All Grade 3+ Adverse Events from Table 4.1 CN Category Adverse Event Grade Neurology Anxiety 3 Olfactory nerve disorder 3 Peripheral motor neuropathy 3 Speech disorder Blood/bone marrow 297 Syndromes Influenza-like illness Metabolic/laboratory Hypokalemia Constitutional symptoms Insomnia Musculoskeletal/soft tissue Muscle weakness, generalized or specific area (not due to 3 neuropathy): Left-sided Neurology Speech disorder Gastrointestinal Nausea 3 Vomiting NOS Blood/bone marrow 312 Pulmonary/upper respiratory Dyspnoea Blood/bone marrow 335 Musculoskeletal/soft tissue Musculoskeletal/soft tissue - Other: Blood/bone marrow Leukopenia NOS Blood/bone marrow 347 Blood/bone marrow Hemoglobin 3 Leukopenia NOS 3 Infection Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 3 10e9/L): Lung (pneumonia) Pulmonary/upper respiratory Pneumonitis NOS Blood/bone marrow Leukopenia NOS Blood/bone marrow Hemoglobin 3 Leukopenia NOS 4 Gastrointestinal Anorexia 3 Dysgeusia 3 Nausea 3 Musculoskeletal/soft tissue Muscle weakness NOS Blood/bone marrow 362 Blood/bone marrow Metabolic/laboratory Hyponatremia Blood/bone marrow Neurology Confusional state Blood/bone marrow Pending Pending Gastrointestinal Vomiting NOS 3 Neurology Memory impairment 3 Pulmonary/upper respiratory Cough 3

15 June Table 4.2 All Grade 3+ Adverse Events from Table 4.1 CN Category Adverse Event Grade 370 Blood/bone marrow Leukopenia NOS 4 Hemorrhage/bleeding Hemorrhagic stroke Gastrointestinal Constipation Blood/bone marrow Hemoglobin Blood/bone marrow Pending Pending Blood/bone marrow Hemoglobin 3 Leukopenia NOS 4 Infection Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 5 10e9/L): Bronchus Metabolic/laboratory Blood bilirubin increased 3 Hypoalbuminemia Vascular Thrombosis Blood/bone marrow Neurology Convulsions NOS Metabolic/laboratory Alanine aminotransferase increased Metabolic/laboratory Alanine aminotransferase increased Blood/bone marrow 399 Blood/bone marrow Infection Febrile neutropenia Blood/bone marrow 416 Blood/bone marrow 419 Blood/bone marrow Allergy/immunology Hypersensitivity NOS Blood/bone marrow 438 Blood/bone marrow 441 Blood/bone marrow 445 Gastrointestinal Anorexia 3 Dehydration Blood/bone marrow 460 Blood/bone marrow 463 Blood/bone marrow 464 Blood/bone marrow 465 Blood/bone marrow 469 Blood/bone marrow Leukopenia NOS 3 Pending Pending Blood/bone marrow

16 June Table 4.2 All Grade 3+ Adverse Events from Table 4.1 CN Category Adverse Event Grade 477 Blood/bone marrow Pain Headache Blood/bone marrow Cardiac general Hypotension NOS 3 Gastrointestinal Dehydration Blood/bone marrow Metabolic/laboratory Alanine aminotransferase increased Blood/bone marrow Gastrointestinal Dysphagia 3 Neurology Ataxia 3 Confusional state 3 Dizziness 3 Peripheral motor neuropathy Neurology Convulsions NOS Blood/bone marrow 512 Neurology Syncope Metabolic/laboratory Hyperglycaemia NOS Blood/bone marrow Neurology Optic nerve disorder NOS Blood/bone marrow 541 Blood/bone marrow 544 Infection Febrile neutropenia Metabolic/laboratory Blood bilirubin increased Blood/bone marrow 551 Constitutional symptoms Insomnia Gastrointestinal Ileus paralytic Blood/bone marrow 569 Constitutional symptoms Fatigue 4 Infection Infectious meningitis 3 Neurology Dizziness 4 Ocular/visual Vision blurred Blood/bone marrow Gastrointestinal Nausea 3 Vomiting NOS 3 Hepatobiliary/pancreas Hepatobiliary/pancreas - Other: 3 Metabolic/laboratory Alanine aminotransferase increased 4 Aspartate aminotransferase increased 3 Blood alkaline phosphatase increased 3 Blood bilirubin increased 3 Gamma-glutamyltransferase increased 4 Musculoskeletal/soft tissue Muscle weakness NOS 3 Neurology Neurology - Other: Gastrointestinal Nausea Blood/bone marrow Leukopenia NOS 3 Metabolic/laboratory Hypokalemia 4

17 June Table 4.2 All Grade 3+ Adverse Events from Table 4.1 CN Category Adverse Event Grade Pending Pending Blood/bone marrow Leukopenia NOS Pulmonary/upper respiratory Pneumonitis NOS Blood/bone marrow Pending Pending Blood/bone marrow Leukopenia NOS Neurology Convulsions NOS Blood/bone marrow Leukopenia NOS Blood/bone marrow 600 Musculoskeletal/soft tissue Muscle weakness, generalized or specific area (not due to 3 neuropathy): Right-sided Neurology Speech disorder Cardiac general Cardiac General - Other: Cardiopulmonary Arrest 5 Infection Infection - Other: 4 Neurology Encephalopathy Blood/bone marrow 611 Blood/bone marrow 612 Blood/bone marrow 618 Vascular Vascular access NOS complication Vascular Thrombosis Blood/bone marrow CD4 lymphocytes decreased 3 Pending Pending Blood/bone marrow Leukopenia NOS Dermatology/skin Alopecia Blood/bone marrow Hemoglobin 3 Leukopenia NOS 3 Metabolic/laboratory Hypocalcemia Blood/bone marrow CD4 lymphocytes decreased 3 Pain Headache Blood/bone marrow Leukopenia NOS Blood/bone marrow Leukopenia NOS 3 Metabolic/laboratory Alanine aminotransferase increased 3

18 June Table 4.2 All Grade 3+ Adverse Events from Table 4.1 CN Category Adverse Event Grade 652 Blood/bone marrow 654 Gastrointestinal Nausea 3 Vomiting NOS Musculoskeletal/soft tissue Musculoskeletal/soft tissue - Other: Vascular Thrombosis Metabolic/laboratory Gamma-glutamyltransferase increased Dermatology/skin Acne NOS Blood/bone marrow 682 Cardiac Arrhythmia Atrial fibrillation 3 Pulmonary/upper respiratory Dyspnoea Blood/bone marrow 689 Allergy/immunology Hypersensitivity NOS 3 Dermatology/skin Dermatitis exfoliative NOS Blood/bone marrow Hemoglobin 3 Metabolic/laboratory Hypoalbuminemia Dermatology/skin Dermatitis exfoliative NOS Gastrointestinal Anorexia Blood/bone marrow 719 Neurology Convulsions NOS Blood/bone marrow Leukopenia NOS Blood/bone marrow Infection Opportunistic infection Blood/bone marrow Leukopenia NOS Dermatology/skin Alopecia 3 Erythema multiforme Blood/bone marrow 737 Pending Pending Blood/bone marrow Hemoglobin 3 Cardiac general Hypotension NOS 3 Coagulation Activated partial thromboplastin time prolonged 3 Gastrointestinal Dehydration 3 Infection Infection with unknown ANC: Urinary tract NOS 3 Metabolic/laboratory Alanine aminotransferase increased 3 Vascular Thrombosis Metabolic/laboratory Hyponatremia Blood/bone marrow CD4 lymphocytes decreased 3 Hemoglobin 3 Musculoskeletal/soft tissue Muscle weakness NOS 3 Vascular Thrombosis 4

19 June Table 4.2 All Grade 3+ Adverse Events from Table 4.1 CN Category Adverse Event Grade 746 Blood/bone marrow 747 Blood/bone marrow Infection Opportunistic infection Blood/bone marrow 757 Blood/bone marrow 758 Blood/bone marrow Infection Opportunistic infection Blood/bone marrow Hemoglobin 3 Leukopenia NOS Gastrointestinal Nausea Dermatology/skin Radiation recall syndrome Dermatology/skin Dermatitis radiation NOS Vascular Vascular access NOS complication Blood/bone marrow Infection Febrile neutropenia Blood/bone marrow 811 Metabolic/laboratory Gamma-glutamyltransferase increased Blood/bone marrow 817 Blood/bone marrow Leukopenia NOS Pain Abdominal pain NOS Blood/bone marrow 823 Blood/bone marrow Metabolic/laboratory Hypophosphataemia Blood/bone marrow 828 Metabolic/laboratory Hyperglycaemia NOS Blood/bone marrow Hemoglobin 3 Leukopenia NOS 4 Hemorrhage/bleeding Epistaxis Blood/bone marrow 836 Gastrointestinal Nausea 3 Vomiting NOS Blood/bone marrow CD4 lymphocytes decreased Gastrointestinal Vomiting NOS Blood/bone marrow 852 Blood/bone marrow 854 Blood/bone marrow Leukopenia NOS 4

20 June Table 4.2 All Grade 3+ Adverse Events from Table 4.1 CN Category Adverse Event Grade 856 Neurology Depression Endocrine Hypothyroidism 3 Neurology Neurology - Other: Blood/bone marrow Metabolic/laboratory Alanine aminotransferase increased Blood/bone marrow 878 Blood/bone marrow 880 Metabolic/laboratory Hyperglycaemia NOS 3 Vascular Vascular access NOS complication Metabolic/laboratory Hypokalemia Metabolic/laboratory Gamma-glutamyltransferase increased Blood/bone marrow 902 Blood/bone marrow 909 Metabolic/laboratory Alanine aminotransferase increased Blood/bone marrow 925 Blood/bone marrow Metabolic/laboratory Alanine aminotransferase increased Pain Headache Pain Back pain Metabolic/laboratory Hypokalemia 3 Hyponatremia Metabolic/laboratory Alanine aminotransferase increased Vascular Vascular access NOS complication Gastrointestinal Mucositis/stomatitis (clinical exam): Anus Renal/genitourinary Renal failure NOS Blood/bone marrow 950 Blood/bone marrow Metabolic/laboratory Hyponatremia Blood/bone marrow 952 Dermatology/skin Radiation recall syndrome Blood/bone marrow Neurology Cerebral ischaemia Blood/bone marrow Gastrointestinal Dehydration 3 Metabolic/laboratory Hyponatremia 3 Pulmonary/upper respiratory Pneumonitis NOS Vascular Thrombosis Blood/bone marrow 966 Blood/bone marrow Leukopenia NOS Pain Headache Blood/bone marrow 973 Blood/bone marrow 977 Blood/bone marrow Coagulation Activated partial thromboplastin time prolonged 3 Metabolic/laboratory Alanine aminotransferase increased 3 Hyperglycaemia NOS 3 Neurology Peripheral motor neuropathy 3

21 June Table 4.2 All Grade 3+ Adverse Events from Table 4.1 CN Category Adverse Event Grade 982 Blood/bone marrow Leukopenia NOS 3 Gastrointestinal Anorexia 3 Stomatitis 3 Infection Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 3 10e9/L): Lung (pneumonia) Pulmonary/upper respiratory Pneumonitis NOS Blood/bone marrow 984 Blood/bone marrow Leukopenia NOS Blood/bone marrow Pain Arthralgia 3 Headache Blood/bone marrow 994 Blood/bone marrow Metabolic/laboratory Alanine aminotransferase increased Blood/bone marrow Hemoglobin 3 Infection Infection with normal ANC or Grade 1 or 2 neutrophils: 5 Wound Metabolic/laboratory Hypocalcemia 3 Hypokalemia 3 Hyponatremia Blood/bone marrow 1001 Blood/bone marrow CD4 lymphocytes decreased Metabolic/laboratory Metabolic/laboratory - Other: 3 Neurology Syncope Blood/bone marrow 1011 Neurology Cognitive disorder 3 Memory impairment 3 Peripheral motor neuropathy Gastrointestinal Nausea 3 Vomiting NOS Blood/bone marrow Leukopenia NOS 3 Constitutional symptoms Fatigue 4 Gastrointestinal Anorexia 3 Infection Gingival infection 3 Neurology Speech disorder Auditory/ear Otitis media serous NOS Blood/bone marrow CD4 lymphocytes decreased 3 Ocular/visual Retinal detachment 3

22 June Table 4.2 All Grade 3+ Adverse Events from Table 4.1 CN Category Adverse Event Grade 1044 Blood/bone marrow Gastrointestinal Colitis NOS 4 Enteritis 5 Infection Infection - Other: 4 Opportunistic infection 4 Pulmonary/upper respiratory Pneumonitis NOS Vascular Vascular access NOS complication Blood/bone marrow 1058 Pulmonary/upper respiratory Dyspnoea 3 Vascular Thrombosis Dermatology/skin Dermatitis exfoliative NOS Blood/bone marrow Hemoglobin 3 Leukopenia NOS Blood/bone marrow 1065 Blood/bone marrow Metabolic/laboratory Hypoalbuminemia Auditory/ear Hearing impaired 3 Neurology Convulsions NOS 4 Neuropathy: cranial: CN VIII Hearing and balance Metabolic/laboratory Gamma-glutamyltransferase increased Pulmonary/upper respiratory Pleural effusion 3 Pneumonitis NOS 3 Vascular Thrombosis Blood/bone marrow 1081 Blood/bone marrow Leukopenia NOS Blood/bone marrow 1092 Blood/bone marrow 1096 Blood/bone marrow 1101 Pending Pending Blood/bone marrow CD4 lymphocytes decreased Blood/bone marrow 1114 Blood/bone marrow Infection Infection - Other: 4 Infection with unknown ANC: Skin (cellulitis) 4 Musculoskeletal/soft tissue Muscle weakness, generalized or specific area (not due to 3 neuropathy): Right-sided Pulmonary/upper respiratory Dyspnoea Neurology Cerebral ischaemia 3

23 June Table 4.2 All Grade 3+ Adverse Events from Table 4.1 CN Category Adverse Event Grade 1120 Neurology Cognitive disorder 4 Confusional state 3 Hydrocephalus acquired 3 Vascular Vascular access NOS complication Blood/bone marrow 1133 Blood/bone marrow Leukopenia NOS Blood/bone marrow Leukopenia NOS 4 Metabolic/laboratory Hypokalemia 3 Musculoskeletal/soft tissue Muscle weakness NOS Neurology Speech disorder Blood/bone marrow 1141 Pulmonary/upper respiratory Pneumonitis NOS 4 Vascular Thrombosis Blood/bone marrow 1151 Blood/bone marrow Leukopenia NOS Blood/bone marrow Leukopenia NOS Blood/bone marrow 1165 Blood/bone marrow

24 June Table 4.3 Adverse Events - Concurrent RT + TMZ Stage Regardless of Relationship to Treatment (n=1120) 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 Pending Pulmonary/upper respiratory Renal/genitourinary Sexual/reproductive function Syndromes Vascular Worst non-hematologic (15%) (35%) (21%) (6%) (3%) Worst overall (13%) (31%) (24%) (12%) (3%)

25 June Table 4.4 Adverse Events - Adjuvant TMZ Reported as Definitely, Probably, or Possibly Related to Treatment * Arm 1 (n=335) Grade Arm 2 (n=361) Grade Category Allergy/immunology Auditory/ear Blood/bone marrow Cardiac Arrhythmia Cardiac general Coagulation Constitutional symptoms Dermatology/skin Endocrine Gastrointestinal Hemorrhage/bleeding Hepatobiliary/pancreas Infection Lymphatics Metabolic/laboratory Musculoskeletal/soft tissue Neurology Ocular/visual Pain Pending Pulmonary/upper respiratory Renal/genitourinary Sexual/reproductive function Vascular Worst non-hematologic (20%) (43%) (14%) (3%) (<1%) (19%) (36%) (23%) (2%) (1%) Worst overall (12%) (39%) (23%) (10%) (1%) (9%) (28%) (37%) (12%) (1%) * Includes adverse events where relationship to treatment is missing

26 June Table 4.5 All Grade 3+ Adverse Events from Table 4.4 RX CN Category Adverse Event Grade Arm 1 45 Gastrointestinal Vomiting NOS 3 Neurology Confusional state 3 Mental status changes 3 Peripheral sensory neuropathy 3 Speech disorder 4 47 Dermatology/skin Dermatitis exfoliative NOS 3 56 Blood/bone marrow 58 Blood/bone marrow 59 Pending Pending 3 64 Infection Bone infection NOS 3 72 Neurology Peripheral motor neuropathy 4 83 Hemorrhage/bleeding Petechiae 3 85 Blood/bone marrow 92 Blood/bone marrow Leukopenia NOS 3 99 Blood/bone marrow 112 Gastrointestinal Colitis NOS 3 Infection Bone infection NOS 4 Infection - Other: 3 Pneumonia NOS Blood/bone marrow Pending Pending Blood/bone marrow Infection Febrile neutropenia Blood/bone marrow Leukopenia NOS Blood/bone marrow Hemoglobin 3 Leukopenia NOS 4 Musculoskeletal/soft tissue Musculoskeletal/soft tissue - Other: 3 Pulmonary/upper respiratory Pneumonitis NOS Blood/bone marrow Leukopenia NOS Blood/bone marrow Hemoglobin 5 Leukopenia NOS 4 Pulmonary/upper respiratory Dyspnoea Blood/bone marrow 243 Blood/bone marrow Leukopenia NOS Blood/bone marrow 251 Blood/bone marrow Leukopenia NOS Blood/bone marrow

27 June Table 4.5 All Grade 3+ Adverse Events from Table 4.4 RX CN Category Adverse Event Grade Arm Blood/bone marrow 270 Blood/bone marrow Hemoglobin 3 Leukopenia NOS 3 Musculoskeletal/soft tissue Muscle weakness NOS Blood/bone marrow 315 Metabolic/laboratory Gamma-glutamyltransferase increased 3 Musculoskeletal/soft tissue Muscle weakness, generalized or specific area (not 3 due to neuropathy): Left-sided 317 Blood/bone marrow Gastrointestinal Diarrhoea NOS Blood/bone marrow 350 Blood/bone marrow 359 Blood/bone marrow CD4 lymphocytes decreased Blood/bone marrow Infection Infection - Other: 3 Neurology Confusional state Neurology Convulsions NOS Infection Infection with normal ANC or Grade 1 or 2 3 neutrophils: Nerve-peripheral Metabolic/laboratory Hypokalemia 3 Musculoskeletal/soft tissue Muscle weakness NOS 3 Neurology Cognitive disorder 3 Optic nerve disorder NOS 3 Pain Neuralgia NOS Infection Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 3 10e9/L): Brain (encephalitis, infectious) 403 Blood/bone marrow 416 Blood/bone marrow CD4 lymphocytes decreased 3 Musculoskeletal/soft tissue Muscle weakness NOS Blood/bone marrow 437 Blood/bone marrow 449 Blood/bone marrow Constitutional symptoms Insomnia Blood/bone marrow Leukopenia NOS 4 Neurology Cerebral ischaemia Blood/bone marrow 462 Neurology Convulsions NOS Blood/bone marrow

28 June Table 4.5 All Grade 3+ Adverse Events from Table 4.4 RX CN Category Adverse Event Grade Arm Blood/bone marrow Vascular Thrombosis Gastrointestinal Nausea Blood/bone marrow Leukopenia NOS Neurology Convulsions NOS Neurology Dizziness Blood/bone marrow Leukopenia NOS 3 Endocrine Hot flushes NOS Gastrointestinal Nausea Blood/bone marrow 557 Blood/bone marrow 574 Blood/bone marrow Neurology Syncope Blood/bone marrow 593 Blood/bone marrow Pain Headache Blood/bone marrow 632 Blood/bone marrow Leukopenia NOS Blood/bone marrow Metabolic/laboratory Hypocalcemia Blood/bone marrow 684 Blood/bone marrow Leukopenia NOS Neurology Personality change Blood/bone marrow 710 Blood/bone marrow 721 Blood/bone marrow Leukopenia NOS Dermatology/skin Alopecia Blood/bone marrow Leukopenia NOS Dermatology/skin Pruritus Musculoskeletal/soft tissue Muscle weakness, generalized or specific area (not 3 due to neuropathy): Left-sided 768 Neurology Hydrocephalus acquired Blood/bone marrow 772 Infection Abdominal infection Blood/bone marrow 779 Blood/bone marrow

29 June Table 4.5 All Grade 3+ Adverse Events from Table 4.4 RX CN Category Adverse Event Grade Arm Blood/bone marrow Hemoglobin Musculoskeletal/soft tissue Muscle weakness NOS Blood/bone marrow Blood/bone marrow - Other: 3 Hemoglobin 3 Leukopenia NOS 4 Infection Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 3 10e9/L): Lung (pneumonia) Metabolic/laboratory Alanine aminotransferase increased Blood/bone marrow CD4 lymphocytes decreased Blood/bone marrow 825 Blood/bone marrow 832 Musculoskeletal/soft tissue Muscle weakness, generalized or specific area (not 3 due to neuropathy): Left-sided Neurology Convulsions NOS 3 Pain Headache Blood/bone marrow CD4 lymphocytes decreased 3 Leukopenia NOS Infection Skin infection Blood/bone marrow Vascular Thrombosis Constitutional symptoms Weight decreased 3 Gastrointestinal Nausea 3 Vomiting NOS Gastrointestinal Nausea 3 Vomiting NOS 3 Infection Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 3 10e9/L): Gallbladder (cholecystitis) 878 Blood/bone marrow 884 Constitutional symptoms Pyrexia Blood/bone marrow 897 Gastrointestinal Nausea 3 Vomiting NOS Gastrointestinal Anorexia Blood/bone marrow 925 Blood/bone marrow Blood/bone marrow 981 Blood/bone marrow 992 Metabolic/laboratory Alanine aminotransferase increased 3

30 June Table 4.5 All Grade 3+ Adverse Events from Table 4.4 RX CN Category Adverse Event Grade Arm Blood/bone marrow Leukopenia NOS 3 Gastrointestinal Diarrhoea NOS 3 Pain Abdominal pain NOS Hepatobiliary/pancreas Cholecystitis NOS 3 Pancreatitis NOS 3 Metabolic/laboratory Alanine aminotransferase increased 3 Aspartate aminotransferase increased 4 Blood amylase increased 3 Blood bilirubin increased 3 Gamma-glutamyltransferase increased Blood/bone marrow 1055 Blood/bone marrow 1069 Neurology Convulsions NOS 3 Speech disorder Blood/bone marrow Leukopenia NOS Blood/bone marrow 1103 Blood/bone marrow Metabolic/laboratory Hyponatremia Metabolic/laboratory Hypokalemia Neurology CNS necrosis/cystic progression: 3 Confusional state Blood/bone marrow CD4 lymphocytes decreased 3 Leukopenia NOS 3 Arm 2 6 Pending Pending 3 Vascular Thrombosis 3 7 Blood/bone marrow Leukopenia NOS 3 8 Pulmonary/upper respiratory Pneumonitis NOS 3 9 Blood/bone marrow Musculoskeletal/soft tissue Muscle weakness NOS 3 13 Metabolic/laboratory Alanine aminotransferase increased 3 Musculoskeletal/soft tissue Muscle weakness NOS Blood/bone marrow Leukopenia NOS 3 Neurology Peripheral motor neuropathy 3 23 Blood/bone marrow 26 Blood/bone marrow 33 Blood/bone marrow 34 Neurology Peripheral motor neuropathy 3 38 Blood/bone marrow 52 Blood/bone marrow 66 Constitutional symptoms Constitutional Symptoms - Other: 3 68 Blood/bone marrow CD4 lymphocytes decreased 4 Leukopenia NOS 3

31 June Table 4.5 All Grade 3+ Adverse Events from Table 4.4 RX CN Category Adverse Event Grade Arm 2 78 Neurology Convulsions NOS 3 79 Blood/bone marrow 89 Blood/bone marrow Leukopenia NOS 3 Pain Arthralgia 3 Neuralgia NOS 3 Pending Pending 3 93 Blood/bone marrow Leukopenia NOS 3 Constitutional symptoms Weight decreased 3 96 Blood/bone marrow Infection Opportunistic infection Blood/bone marrow Pain Headache Blood/bone marrow Neurology Convulsions NOS 3 Peripheral sensory neuropathy Blood/bone marrow 109 Blood/bone marrow Blood/bone marrow - Other: 3 Hemorrhage/bleeding Hemorrhage/bleeding - Other: 3 Metabolic/laboratory Alanine aminotransferase increased 3 Hyperglycaemia NOS 3 Musculoskeletal/soft tissue Muscle weakness, generalized or specific area (not 3 due to neuropathy): Extremity-lower Vascular Vascular access NOS complication Musculoskeletal/soft tissue Muscle weakness NOS Blood/bone marrow Leukopenia NOS Blood/bone marrow Leukopenia NOS Gastrointestinal Anorexia 3 Dehydration 3 Musculoskeletal/soft tissue Muscle weakness NOS 3 Neurology Ataxia Gastrointestinal Gastritis NOS Blood/bone marrow 160 Blood/bone marrow 188 Blood/bone marrow Gastrointestinal Anorexia 3 Infection Opportunistic infection 3 Musculoskeletal/soft tissue Muscle weakness NOS 4 Neurology Cognitive disorder Blood/bone marrow 192 Blood/bone marrow Gastrointestinal Nausea 3 Pending Pending 3

32 June Table 4.5 All Grade 3+ Adverse Events from Table 4.4 RX CN Category Adverse Event Grade Arm Blood/bone marrow 207 Blood/bone marrow Leukopenia NOS 3 Metabolic/laboratory Alanine aminotransferase increased Blood/bone marrow Gastrointestinal Dehydration 3 Nausea 3 Vomiting NOS Blood/bone marrow 225 Blood/bone marrow Blood/bone marrow - Other: 3 Leukopenia NOS Pain Headache Blood/bone marrow CD4 lymphocytes decreased 3 Infection Skin infection Blood/bone marrow CD4 lymphocytes decreased Blood/bone marrow Leukopenia NOS Blood/bone marrow CD4 lymphocytes decreased Neurology Cerebral ischaemia Blood/bone marrow 309 Blood/bone marrow CD4 lymphocytes decreased 3 Gastrointestinal Nausea Blood/bone marrow 316 Blood/bone marrow Leukopenia NOS 3 Pending Pending Blood/bone marrow Hemoglobin 3 Leukopenia NOS 4 Infection Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 3 10e9/L): Lung (pneumonia) 330 Blood/bone marrow Leukopenia NOS Neurology Memory impairment Blood/bone marrow

33 June Table 4.5 All Grade 3+ Adverse Events from Table 4.4 RX CN Category Adverse Event Grade Arm Blood/bone marrow Metabolic/laboratory Alanine aminotransferase increased 3 Aspartate aminotransferase increased 3 Pulmonary/upper respiratory Acute respiratory distress syndrome 5 Pneumonitis NOS 4 Renal/genitourinary Renal failure NOS Blood/bone marrow CD4 lymphocytes decreased 4 Pending Pending Blood/bone marrow Pending Pending Blood/bone marrow 374 Gastrointestinal Anorexia 3 Infection Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 3 10e9/L): Bladder (urinary) Musculoskeletal/soft tissue Muscle weakness NOS Blood/bone marrow CD4 lymphocytes decreased 3 Neurology Convulsions NOS Neurology Dizziness Blood/bone marrow 386 Pulmonary/upper respiratory Pneumonitis NOS Blood/bone marrow CD4 lymphocytes decreased 3 Leukopenia NOS Gastrointestinal Anorexia 3 Nausea Vascular Thrombosis Blood/bone marrow Pending Pending Blood/bone marrow Leukopenia NOS Pain Headache Blood/bone marrow 424 Blood/bone marrow Leukopenia NOS Neurology Convulsions NOS Blood/bone marrow CD4 lymphocytes decreased Ocular/visual Vision blurred Blood/bone marrow Cardiac Arrhythmia Atrial fibrillation 3 Supraventricular extrasystoles 3 Infection Opportunistic infection Blood/bone marrow

34 June Table 4.5 All Grade 3+ Adverse Events from Table 4.4 RX CN Category Adverse Event Grade Arm Blood/bone marrow 477 Blood/bone marrow CD4 lymphocytes decreased 3 Gastrointestinal Anorexia 3 Dehydration Blood/bone marrow Blood/bone marrow 513 Blood/bone marrow 518 Blood/bone marrow 519 Blood/bone marrow Hemoglobin 3 Infection Infection with normal ANC or Grade 1 or 2 3 neutrophils: Wound 541 Blood/bone marrow Blood/bone marrow 549 Gastrointestinal Anorexia 3 Nausea Metabolic/laboratory Hyponatremia Blood/bone marrow Infection Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 3 10e9/L): Lung (pneumonia) 566 Pending Pending Gastrointestinal Nausea Blood/bone marrow Leukopenia NOS Blood/bone marrow 588 Blood/bone marrow Neurology Cerebral ischaemia Blood/bone marrow 604 Blood/bone marrow 611 Musculoskeletal/soft tissue Muscle weakness NOS 3 Pending Pending Blood/bone marrow CD4 lymphocytes decreased 4 Leukopenia NOS 3 Metabolic/laboratory Gamma-glutamyltransferase increased Blood/bone marrow 629 Blood/bone marrow 634 Blood/bone marrow 642 Blood/bone marrow Neurology Dizziness Blood/bone marrow CD4 lymphocytes decreased 3