January 2011 0834-1 EORTC 26053 22054 (RTOG 0834 Endorsed) Protocol Status: Opened: July 22, 2009 Title: Phase III Trial on Concurrent and Adjuvant Temozolomide Chemotherapy in Non-1P/19Q Deleted Anaplastic Glioma: The CATNON Intergroup Trial Patient Population: Patients must have histologically confirmed newly diagnosed anaplastic oligodendroglioma, anaplastic oligoastrocytoma or anaplastic astrocytoma and absence of combined 1p/19q loss. Objectives: Schema: Primary: To assess whether concurrent radiotherapy with daily temozolomide chemotherapy improves overall survival as compared to no daily temozolomide in patients with non-1p/19q deleted anaplastic glioma. To assess whether adjuvant temozolomide chemotherapy improves survival as compared to no adjuvant temozolomide chemotherapy in patients with non-1p/19q deleted anaplastic glioma. Secondary: To assess whether concurrent and adjuvant temozolomide treatment prolongs progression free survival and neurological deterioration free survival in patients with non-1p/19q deleted anaplastic glioma. To assess the safety of concurrent and adjuvant temozolomide in patients with non-1p/19q deleted anaplastic glioma, including late effects on cognition. To assess the impact of concurrent and adjuvant temozolomide treatment on the quality of life in patients with non-1p/19q deleted anaplastic glioma. North American institutions should refer to the appropriate Group Specific Appendix on the CTSU menu for supplemental enrollment logistics. Institution must choose to evaluate 1p/19q LOH locally or use central facility. After registration, all material is centrally reviewed for MGMT methylation status. * Investigators can t randomize a patient: If the central facility is used: before the histological diagnosis, diagnosis of no combined 1p/19q LOH has been centrally confirmed and the MGMT methylation status (methylated/unmethylated or indeterminate) has been communicated by the EORTC Data Centre. The randomization is based on the central histological and 1p/19q LOH evaluation. If the local assessment is used: before the MGMTmethylation status (methylated/unmethylated or indeterminate) has been communicated by the EORTC Data Centre. The randomization is based on the local histological and 1p/19q LOH evaluation.
January 2011 0834-2 Coordinating Group: EORTC BTG Patients entered through10/14/10: Study 318 RTOG 22 Participants: EORTC ROG, RTOG, NCIC-CTG, CTSU, MRC-CTU, COGNO Collaborative Groups/Co-Chairs: EORTC Brain Tumor Group/W. Wick, A. Omuro, R. Soffietti EORTC Radiation Oncology Group/ B. Baumert NCI-C/ J.G. Cairncross, W. Mason RTOG/M. Metha, M. Vogelbaum MRC/M. Brada HUB/S. Grossman, K. Jaeckle Study Chairman: Martin van den Bent I. Summary: This EORTC 26053-22054 study is a CATNON Intergroup Trial. This study activated in Dec, 2007, with the target accrual of 748 patients. RTOG endorsed this study and opened to accrual on July 22, 2009 in North America. As of October 14, 2010, a total of 318 patients enrolled to this study. Section II gives detailed accrual information. Section III presents patient characteristics information. The adverse information is presented in the Section IV.
January 2011 0834-3 II. Administrative Information: Accrual graph of Registered patients Accrual of study 26053 - REGISTRATION 700 650 600 550 Theoretical Study Expected today: 380 Observed today: 318 Number of patients 500 450 400 350 300 250 Expected 1y: 100 Observed 1y: 88 Expected 2y: 250 Observed 2y: 213 200 150 100 50 0 4/03/08 4/03/09 4/03/10 Time 4/03/11 3/03/12 3/03/13 Accrual graph of Randomized patients with an estimated fall out of 10% between Registration and Randomization Accrual of study 26053 - RANDOMIZATION 650 600 Theoretical Study 550 500 Expected today: 342 Observed today: 177 Number of patients 450 400 350 300 250 200 Expected 1y: 108 Observed 1y: 55 Expected 2y: 243 Observed 2y: 122 150 100 50 0 4/03/08 4/03/09 4/03/10 Time 4/03/11 3/03/12 3/03/13 Participating groups Number of patients EORTC BTG EORTC BTG/ROG EORTC ROG CTSU (*) RTOG NCIC- CTG COGNO MRC Total Registered 52 (16.4%) 220 (69.2%) 10 (3.1%) 3 (.9%) 22 (6.9%) 3 (.9%) 7 (2.2%) 1 (.3%) 318 (100%) Randomized 22 (12.4%) 136 (76.8%) 4 (2.3%) 0 (0%) 10 (5.6%) 2 (1.1%) 3 (1.7%) 0 (0%) 177 (100%) (*) CTSU group is composed of North American institutions not affiliated to RTOG or NCIC-CTG
January 2011 0834-4 RTOG Institutional Accrual by Submitting Institution on randomized patients (n=10) M D Anderson Cancer Center 2 Abington Memorial Hospital 1 Henry Ford Hospital 1 Intermountain Medical Center 1 LDS Hospital 1 Thomas Jefferson University Hospital 1 University of Florida 1 University of Rochester 1 University of Wisconsin Hospital and Clinics 1 Reason for no randomization (based on validated, pending and on hold End of Treatment forms) Nb of Patients (n=92) Histology and/or 1p/19q co-deletion not confirmed 67 Refusal 19 Other* 6 *Other: SeqID 97 - logistic difficulties/ problems *Other: SeqID 118 - The patient did not want to wait the EORTC green light to start with radiation. (begin: 26/03/2009) *Other: SeqID 130 - EMPTY *Other: SeqID 179 - necessary IMRT + loss of both 1p/19q *Other: SeqID 244 - EMPTY *Other: SeqID 292 - EMPTY
January 2011 0834-5 III. Pretreatment Characteristics: Performance status Age 1p LOH 19q LOH Oligodendroglial elements MGMT Table 3.1 Baseline characteristics of Randomized patients (N=162) RT n=41 RT + conc. TMZ n=40 RT + adj. TMZ n=40 RT + conc. TMZ + adj. TMZ 0 20 22 24 23 1-2 21 18 16 18 <=50 29 26 30 27 >50 12 14 10 14 Range 21.6-72.5 23.7-74.8 20.0-74.6 23.2-71.3 Median 42.9 45.5 43.1 44.1 no Loss 38 37 36 38 LOH 1 2 4 3 Undeterminable 2 1 - - no Loss 31 35 33 36 LOH 10 5 6 5 Undeterminable - - 1 - no 27 25 26 26 yes 14 15 14 15 Methylated 4 3 3 1 Unmethylated 13 10 14 15 Indeterminate 24 27 23 25 n=41 Table 3.2 Overall Compliance to QOL (allowing for 3 months delay) Only patients on study for at least 3 months are displayed Per visit Assessment time Nb forms Received Nb forms Expected % compliance Baseline 95 144 66.0 4 Week after RT 65 124 52.4 3M visit 52 96 54.2 6M visit 28 75 37.3 9M visit 17 54 31.5 12M visit 10 40 25.0 15M visit 10 30 33.3 18M visit 8 19 42.1
January 2011 0834-6 IV. Adverse Events: Table 4.1 Hematological Events Hematological events (based on 80 patients with validated and pending data) grade 3 No adverse event > grade 3 was reported RT RT + conc. TMZ RT + adj. TMZ RT + conc. TMZ + adj. TMZ (n=20) (n=17) (n=22) (n=21) grade 3 grade 3 grade 3 grade 3 WBC - - 2 (9.1%) 2 (9.5%) ANC - - 2 (9.1%) 2 (9.5%) Platelets - 1 (5.9%) 1 (4.5%) 1 (4.8%) Hemoglobin - - - - Table 4.2 Observed Adverse Events Adverse events (based on 79 patients validated and pending data) grade 3 No adverse event > grade 3 was reported RT RT + conc. TMZ RT + adj. TMZ RT + conc. TMZ + adj. TMZ (n=20) (n=17) (n=22) (n=20) grade 3 grade 3 grade 3 grade 3 Allergic reaction - - - 1 (5.0%) Fatigue - 2 (11.8%) 2 (9.1%) 1 (5.0%) Alopecia 2 (10.0%) 1 (5.9%) 1 (4.5%) - Anorexia - 1 (5.9%) - - Nausea - - 1 (4.5%) - Febrile neutropenia - - 1 (4.5%) - Cognitive Disturbance - 1 (5.9%) - - Mood alteration - - - 1 (5.0%) Seizures 1 (5.0%) 2 (11.8%) 2 (9.1%) 2 (10.0%) Neuropathy: motor - 4 (23.5%) 1 (4.5%) - Neuropathy: sensory - 2 (11.8%) - -
January 2011 0834-7 Other adverse events grade 3 for Arm 1: RT alone (n = 79 - validated and pending data) No baseline data included SeqID Event Grade reported 5 AUD Hearing 3 Other adverse events grade 3 for Arm 2: RT + conc. TMZ (n = 79 - validated and pending data) No baseline data included SeqID Event Grade Reported 10 NEU Speech Impairment 3 36 BLO Platelets 3 36 CON Insomnia 3 36 NEU OTH CNS after surgery partial media infarct right 3 36 Neurology cranial facialis paresis, visual inattention, anopsis left 3 36 Cranial Facietis Parese, hemianopsie left 3 55 hemiparesis 3 55 NEU Speech impairment 3 55 CON Weight gain 3 60 MET Hyperglycemia 3 64 INF OTH Septicaemia 3 Other adverse events grade 3 for Arm 3: RT + Adj. TMZ (n = 79 - validated and pending data) No baseline data included SeqID Event Grade reported 56 With normal ANC Pseudomonas aeruginoza 3 75 Incontinence of urine 3 Other adverse events grade 3 for Arm 4: RT + conc. TMZ + Adj. TMZ (n = 79 with validated and pending data) No baseline data included SeqID Event Grade Reported 3 BLO Platelets 3 50 BLO Lymphopenia 3 77 INF GEN Wound 3 77 NEU Syncope (fainting) 3 163 NEU Ataxia 3
January 2011 0834-8 SOC PT RT Table 4.3 Serious adverse events (based on all data) Cumulative Summary Tabulations SAEs (cut-off date: 09/08/2010) RT + conc. TMZ RT + adj. TMZ RT + conc. TMZ + adj. TMZ Eye disorders Retinal detachment 1 1 General disorders and administration site conditions Grand Total Eye disorders Total 1 1 General disorders and administration site conditions Total Gait disturbance 1 1 1 1 Hepatobiliary disorders Hepatitis toxic 1 1 Hepatobiliary disorders Total 1 1 Immune system disorders Hypersensitivity 1 1 Immune system disorders Total 1 1 Infections and infestations Infection 1 1 Pneumonia 1 1 Wound infection 1 1 Infections and infestations Total 2 1 3 Metabolism and nutrition disorders Hyponatraemia 1 1 Metabolism and nutrition disorders Total 1 1 Nervous system disorders Brain oedema 1 1 Convulsion 7 1 8 Dizziness 1 1 Epilepsy 1 1 Hemiparesis 1 1 Intracranial hypotension 1 1 Nervous system disorders Total 4 8 1 13 Grand Total 7 9 1 4 21 Cumulative Summary Tabulations SARs (cut-off date: 09/08/2010) SOC PT RT RT + conc. TMZ RT + adj. TMZ RT + conc. TMZ + adj. TMZ Hepatobiliary disorders Hepatitis toxic 1 (*) 1 Hepatobiliary disorders Total 1 1 Immune system disorders Hypersensitivity 1 1 Immune system disorders Total 1 1 Infections and infestations Pneumonia 1 1 Infections and infestations Total 1 1 Nervous system disorders Brain oedema 1 1 Grand Total Convulsion 7 1 8 Hemiparesis 1 1 Nervous system disorders Total 1 8 1 10 Grand Total 2 8 1 2 13 (*) SUSAR