Cancer Treatment Trials:

Transcription

1 Neuro-Oncology Program The NCCTG Neuro-Oncology program contains three project areas: (1) cancer treatment trials, (2) neurobehavioral studies, and (3) translational research. Cancer Treatment Trials: Glioblastoma (grade 4 astrocytoma): N0074, "Phase II Study of ZD1839 (NSC ) in Patients With Newly Diagnosed Glioblastoma" remains open to patient accrual. To date, accrual is proceeding ahead of projections. ZD1839 is an oral epidermal growth factor receptor (EGFR) inhibitor. In many glioblastoma patients, EGFR is amplified and mutated. By inhibiting this abnormal protein, ZD1839 may prolong survival. Following completion of radiation therapy, patients will be registered to the trial and begin ZD1839. N997D: "Pilot and Phase II Trial of CPT-11 and Radiation Followed by CPT-11 and BCNU in Glioblastoma Multiforme Patients" has been approved and by NCI and contractural issues finalized. This protocol explores the potential benefit of additive interactions of weekly CPT-11 during radiation, followed by combination CPT-11 and BCNU for following radiation. A pilot study will explore the safety and dosing for patients who are receiving or not receiving enzyme inducing (microsomal p450, CYP 3A4) anticonvulsants (EIAC vs non-eiac). The pilot portion of the study will be activated concurrently with N0074. The phase II portion will be activated upon completion of N0074. N0177 "Pilot and Phase II Trial of OSI-774 and Radiation in Glioblastoma Multiforme Patients" concept was approved last year by NCI, and the protocol is currently at CTEP for final review. The pilot portion of the trial will open concurrently with the Phase II portion of N997D. OSI-779, like ZD1839, is an EGFR inhibitor. Preclinical data suggest that EGFR inhibitors enhance the radiosensitivity of tumor cells. In this trial, OSI-779 will be given concurrently with radiation therapy to take advantage of its radiosensitizing properties. Like N997D, this study will include separate strata for patients receiving or not receiving EIACs. Both N997D and N0074 are on track for activation in the near future. All three studies contain pharmacokinetic and/or tranlational tissue correlative analyses. Anaplastic Astrocytoma (grade 3 astrocytoma): NCCTG has activated the intergroup trial, R9813: A Phase I/III Randomized Study of Radiation Therapy and Temozolomide versus Radiation Therapy and BCNU versus Radiation Therapy and Temozolomide and BCNU for Anaplastic Astrocytoma. This study is temporarily closed for assessment of toxicity of the combination per protocol on the first phase, and is expected to re-open in approximately April. R9813 is an intergroup trial involving RTOG, NCCTG, ECOG, and SWOG. The goal of the trial is to determine if temozolomide alone or in combination with BCNU can prolong survival compared with adjuvant BCNU alone. Anaplastic Oligodendroglioma and Oligoastrocytoma (grades 3 and 4): NCCTG (RTOG 9402), "Phase III Intergroup Randomized Comparison of Radiation Alone Versus Preradiation Chemotherapy for Pure and Mixed Anaplastic Oligodendrogliomas" compares radiation alone with preirradiation chemotherapy using procarbazine, CCNU, and vincristine (PCV) followed by radiation to determine if there is improvement in time-to-progression and survival when PCV is added prior to radiation. This protocol has nearly completed accrual. NCCTG has contributed over 10% of the patients to this intergroup trial between NCCTG, SWOG, RTOG and ECOG. Low-Grade Glioma (grades 1 and 2): R9802: A Phase II Study of Observation in Favorable Low Grade Glioma and Phase III Study of Radiation With or Without PCV Chemotherapy in Unfavorable Low Grade Glioma continues to accrue patients. High risk patients (less than total resection or more than 40 years old) are randomized either to radiation alone or radiation followed by 6 cycles of PCV. Low risk patients are observed without further treatment until progression. This study represents the major national effort to

2 assess the value of adjuvant chemotherapy for low grade glioma patients and has accrued over 250 patients, with NCCTG contributing over 10% of patients to this multigroup effort with RTOG, SWOG and ECOG. Recurrent Glioma NCCTG : "Phase I/II Study of Pyrazoloacridine and Carboplatin in Patients with Brain Tumors" is active and accruing on schedule. Patients with recurrent glioma of any histologic type (GM, AA, AO, mixed glioma) are eligible for the trial. The trial was recently amended to expand eligibility for patients with two prior chemotherapy regimens (as adjuvant and at relapse). N997B, A Phase II Study of CCI-779 in Patients with Recurrent Glioblastoma Multiforme, is open for patients with recurrent glioblastoma only. This study includes a pilot arm for pharmacokinetic studies, and several translational correlative tissue investigations. Accrual is on schedule. The concept for N0272, " Phase II Trial of Imatinib Mesylate; (Gleevec; STI571) In Treatment of Recurrent Oligodendroglioma and Mixed Oligoastrocytoma" has been approved by CTEP, and the protocol is being submitted to NCI. This will be a single arm trial with separate strata for EIAC and non EIAC patients, and contains significant translational biologic and pharmacokinetic components. Primary Lymphoma NCCTG : "Primary Central Nervous System Non- Hodgkins Lymphoma (PL): A Phase II Clinical Trial of Radiation Therapy and High-Dose Corticosteroids for Elderly Patients (70 Years of Age and Older)" remains open. Additional patients are needed to complete this study. Neurobehavioral Studies A companion protocol to study fatigue, depression, excessive daytime somnolence and quality of life (QOL) in high-grade glioma patients has been activated in conjunction with , and N0074. Sufficient numbers of the questionnaires with these three studies will be available to answer the questions posed in this trial. A concept has been generated to assess pharmacologic intervention in brain tumor patients with fatigue and impaired cognitive function. In addition, N0076: "Cognitive Status in High Grade Glioma Patients" has been developed to review the impact on cognition of the disease and treatment in more than 1200 patients for whom we have serial Mini-Mental status examinations. Translational Studies NCCTG : "Diagnostic and Prognostic Markers in Anaplastic Astrocytoma and Anaplastic Oligoastrocytoma" continues to be active. NCCTG : "Diagnostic and Prognostic Markers in Low-Grade Gliomas" also remains active. Analysis will be correlated with clinical endpoints in the trial. NCCTG : "Clinical Significance of Histologic Typing in High-Grade Glioma". Two projects remain within this master protocol. Analysis of the relationship between anaplastic oligoastrocytoma compared with anaplastic astrocytoma and glioblastoma is under way. Analysis of subtypes of astrocytoma (small cell, giant cell, fibrillary, etc.) is also in progress. The manuscript describing the results of genetic studies from NCCTG ( 50 Gy vs. 65 Gy) is in press, and the manuscript involving gene studies from NCCTG (RT + PCV) is being finalized. Translational basic science studies accompany nearly all of the active protocols, and new approved concepts, including N0074, NCCTG , N0177, N997D, and N0272. Database Studies NCCTG : "Classification and Regression Tree (CART) Models of Time to Pro-

3 gression and Overall Survival in Patients with Recurrent Glioma" was presented at the Annual Meeting of the Society for Neuro-Oncology in November This analysis identified that duration from initial diagnosis to study registration was a significant prognostic factor, which correlated with time-to-progression and overall survival, and outweighed traditional histologic grade as a prognostic variable. This suggests that the prior natural biology (particularly time course) of the disease has a strong impact upon time-toprogression and overall survival, which has not been given adequate attention in the generation of grouping factors in clinical trials of gliomas. Additional database mining studies are in progress.

4 Program Status Reports for NEURO-ONCOLOGY - April 2002 Neuro-Oncology (RTOG 9402) Phase III Intergroup Randomized Comparison of RadiationAlone Versus Preradiation Chemotherapy for Pure and Mixed AnaplasticOligodendrogliomas Phase II Trial of Chemotherapy Plus Radiotherapy for Management ofprimary Central Nervous System Non-Hodgkin's Lymphoma (PL) Phase III Trial of BCNU and CDDP Versus BCNU Alone and Standard RTVersus Accelerated Hyperfractionated RT in Patients With High GradeGlioma Diagnostic and Prognostic Markers in Anaplastic Astrocytoma andanaplastic Oligoastrocytoma Clinical Significance of Histologic Typing of High-Grade Glioma Diagnostic and Prognostic Markers in Low-Grade Glioma Factors Associated With, Response, Time to Progression and Overall- Survival in Recurrent Glioma Phase II Trials Primary Central Nervous System Non-Hodgkin's Lymphoma (PL): A PhasII Clinical Trial of Radiation Therapy and High Dose Corticosteroidsfor Elderly Patients (70 Years of Age and Older) A Phase II Trial of Irinotecan in Recurrent Glioma R9802 A Phase II Study of Observation in Favorable Low-Grade Gliomas and aphase III Study of Radiation With or Without PCV Chemotherapy inunfavorable Low-Grade Glioma A Phase II Trial of Pre-irradiation Chemotherapy With BCNU, Cisplatinand Oral Etoposide Combined With Radiation Therapy in the Treatment ofgrade 3 Astrocytoma (Anaplastic Astrocytoma) A Phase II Trial of Preirradiation Chemotherapy With BCNU, Cisplatin,and Oral Etoposide Combined With Radiation Therapy in the Treatment ofgrade 4 Astrocytoma (Glioblastoma) Phase I/II Trial of Pyrazoloacridine and Carboplatin in Patients withrecurrent Glioma NCCTG Committee Table of Contents - Page 1 of 2

5 Program Status Reports for NEURO-ONCOLOGY - April 2002 N997B A Phase II Study of CCI-779 in Patients With Recurrent Glioblastoma- Multiforme A Phase I/III Randomized Study of Radiation Therapy and TemozolomideVersus Radiation Therapy and BCNU Versus Radiation Therapy andtemozolomide and BCNU for Anaplastic Astrocytoma N0074 N007D Phase II Study of ZD1839 (NSC ) in Patients with Newly DiagnosedGlioblastoma (Grade 4 Astrocytoma) Validation of a Measurement Method for Intracranial Glial Tumors Other Closed Trials Evaluation of Postoperative Radiation in Low-Grade IntracranialAstrocytoma and Oligodendrogliomas M/N - Phase III Study of Radiation Therapy Plus BCNU With or WithoutRecombinant Interferon Alpha in the Treatment of Newly DiagnosedHigh-Grade Glioma Phase II Study of Preirradiation PCV Chemotherapy in Patients WithSupratentorial Low-Grade Gliomas Protocol Concepts N997D N0177 N017A N0272 Pilot and Phase II Trial of Irinotecan and Radiation Followed byirinotecan and BCNU in Glioblastoma Multiforme Patients A Phase I/II Study of OSI-774 in Combination with Radiation Therapy inglioblastoma Multiforme Treatment of Cognitive Impairment with Donepezil in Patients with- Brain Tumors: A Multidisciplinary Pilot Study Phase II Trial of STI-571 in Treatment of Recurrent Oligodendrogliomaand Mixed Oligoastrocytoma NCCTG Committee Table of Contents - Page 2 of 2

6 NCCTG Status Report for Study April 2002 (RTOG 9402) Phase III Intergroup Randomized Comparison of Radiation Alone Versus Preradiation Chemotherapy for Pure and Mixed Anaplastic Oligodendrogliomas Purpose of Study: 1) To determine overall survival (primary endpoint). 2) To compare time to tumor progression between the study arms. 3) To examine the frequency of severe (grade 3-5) toxicities. 4) To compare quality of life and neurologic function between the treatment arms. 5) To identify the key histopathologic criteria necessary to make the diagnosis of anaplastic oligodendroglioma and mixed oligoastrocytoma, evaluate the diagnostic relevance of chromosomal alterations, evaluate the diagnostic and prognostic relevance of DNA ploidy. Study Chairs: Jan C. Buckner M.D. Paul L. Schaefer M.D. Richard L. Deming M.D. Data Monitor: Butch K. Kvittem Statistician: Nurse Resource: Status: 08/12/1994 Activated Projected Number of Patients: 292 Excluded: None Final Accrual: NA Stratification Age Karnofsky Performance Score Factors: Tumor Grade Schema: Randomize 1) I-PCV x 4 cycles --> RT 2) RT alone Treating Schedule: Arm Agent Dose Route Days Freq 1 CCNU 130 mg/m2 PO Day 1 Every 6 wks X 4 cycles 1 VCR 1.4 mg/m2 IV Day Every 6 wks X 4 cycles 1 PCBZ 75 mg/m2 PO Days 8-21 Every 6 wks X 4 cycles Arm Dose Days FX/Day FX/Size # FX RT Length * 50.4 GY M-F GY /2 wks + 9 GY M-F GY 5 1 wk # 59.4 GY /2 WKS NCCTG Committee Page 1 of 2

7 NCCTG Status Report for Study April 2002 Both Arms 1 & 2 receive RT * Initial volume: T2-MRI + 2cm + Boost volume: T1 (gad) MRI + 1 cm # Total RT information Study Design: This RTOG-led intergroup trial has a standard randomized 2-arm phase-iii study design. Accrual: This trial was activated on 7/1/94 and had accrued 290 patients (99% of the accrual target of 292) as of 11/30/01. With an average accrual rate of 3.3 per month, the study is expected to complete accrual by 3/31/2002. Accrual by NCCTG memberships is summarized in the Accrual Table below. Patient Characteristics: No information provided. Study Status: Accrual is expected to be terminated on or before 3/31/02. Additional Information: No information provided. Accrual Table: Randomizing Membership Total Entered Past 6 Months Past 12 Months Ann Arbor Bismarck Cedar Rapids Des Moines Fargo Geisinger Mayo Peoria St. Cloud Toledo Total Membership Accrual NCCTG Committee Page 2 of 2

8 NCCTG Status Report for Study April 2002 Phase III Trial of BCNU and CDDP Versus BCNU Alone and Standard RT Versus Accelerated Hyperfractionated RT in Patients With High Grade Glioma Purpose of Study: 1) To compare survival distributions of (a) patients treated with AHRT vs SRT and (b) patients treated with BCNU + CDDP before, during & after radiation therapy vs patients treated with BCNU during & after RT. 2) The secondary goals are to compare progression-free & toxicity distributions of patients treated with AHRT vs SRT, and to compare the progression-free & toxicity distributions of patients treated with BCNU + CDDP before, during & after radiation therapy vs patients Study Chairs: Jan C. Buckner M.D. John C. Michalak M.D. Data Monitor: Butch K. Kvittem Statistician: Judith R. O'Fallon Ph.D. Nurse Resource: Gwen Finck R.N. Status: 11/01/ /18/1999 Activated Perm. Closed Projected Number of Patients: 404 Excluded: 50 Final Accrual: 451 Stratification Age Group Histology Factors: Extent of Surgery Performance Score Schema: Randomize A) BCNU + standard RT B) BCNU + accelerated RT C) BCNU + CDDP + standard RT D) BCNU + CDDP + accelerated RT Treating Schedule: Arm Agent Dose Route Days Freq * BCNU 200 mg/m2 IV infusion over at least 1 Every 8 wks X 6 cycles 90 min in glass bottle # BCNU 50 mg/m2/day IV infusion over 1 hr in glass bottles immed. before CDDP 1-3 Every 8 wks X 2 cycles (cycles 1 & 2) # CDDP 30 mg/m2/day IV over 1-2 hrs Every 8 wks X 2 cycles # BCNU 200 mg/m2/day IV infusion over at least 90 min in glass bottles. 1 Every 8 wks X 4 cycles (cycles 3-6) Arm Dose Days FX/Day FX/Size # FX RT Length CGY M-F CGY 36 Approx 7 wks NCCTG Committee Page 1 of 8

9 NCCTG Status Report for Study April 2002 Arm Dose Days FX/Day FX/Size # FX RT Length $ 4800 CGY M-F 2, separated by at least 6 hrs 160 CGY 30 Approx 3 wks Chemotherapy * Arms A & B. Radiation begins with cycle 1 BCNU. # Arms C & D. Radiation For Arms A & B, radiation begins within 72 hrs of random & concurrentl chemo For Arms C & D, radiation begins 8 wks after randomization. + Arms A & C. $ Arms B & D. Study Design: This is a stratified, randomized phase III trial in patients with newly-diagnosed grade-4 astrocytoma (GBM). It has a 2 x 2 design to answer two primary questions regarding the effects of [i] Accelerated Hyperfractionated Radiation Therapy (AHRT) vs. Standard Radiation Therapy (SRT) and [ii] chemotherapy with a BCNU+CDDP combination given before, during, and after RT vs. the usual BCNU chemotherapy given during and after RT. Secondary goals are to compare the distributions of toxicity and time-to-progression among treatment groups. Accrual: The trial was activated by NCCTG on 11/1/94 and by SWOG in June When SWOG joined, the sample size was increased from 280 (70 per arm) to 404 (101 per arm) in order to increase the power to detect any chemotherapy-by-radiotherapy interactions while still completing accrual in 4 years. The first patient was randomized on 12/16/94. The trial was closed to accrual on 6/18/99 after 451 patients had been accrued (251 from 20 NCCTG memberships, 200 from 42 SWOG memberships). Accrual by membership is summarized in the Accrual Table below. Patient Characteristics: As shown in the Baseline Patient Characteristics Table below, most of the 401 eligible noncancelled participants are middle-aged (57%), male (63%), with ECOG PS=0-1 (86%), and were on corticosteroids at study entry (77%). Over half (54%) had a subtotal resection. Only 9 (2%) had gliosarcoma histology. A total of 21 (4.7%) of the 451 entrants were classified as ethnic minorities, but 5 were subsequently ruled ineligible, leaving 16 (4%) of the 401 noncancelled eligibles. NCCTG Committee Page 2 of 8

10 NCCTG Status Report for Study April 2002 Available Information: As of 2/18/02, 50 (11%) of the 451 registered patients have been disqualified (13/111 A, 7/110 B, 17/117 C, 13/113 D); 45 were declared ineligible upon pathology or scan review, and 5 were classified as cancellations. The computer files contain baseline patient characteristics for all 401 eligible noncancelled patients (98 A, 103 B, 100 C, 100 D), while evaluation information is still missing for 2 (0.5%) of them. Currently, 13 (3%) are still on study, 15 (4%) are alive off study therapy, 348 (87%) have progressed, and 373 (93%) have died. Adverse Events: Hematologic Toxicity - With hematologic toxicity data available for 378 patients (93 A, 95 B, 94 C, 96 D), no grade-5 hematologic toxicity has been seen. Grade-4 leukopenia (WBC nadir <1.0) has been reported for 21 (5%) (7 A, 4 B, 3 C, 7 D), and grade-4 thrombocytopenia (PLT nadir <10.0) has been seen in 6 (1.5%) (1 A, 1 C, 4 D). One Arm-D patient had both. Thus the percentages of grade-4 hematologic toxicity are 8.6%, 4.2%, 4.3%, and 10.4% for Arms A-D, respectively. Nonhematologic Toxicity (see Adverse Events Table below) - With nonhematologic toxicity data available for 399 patients (98 A, 102 B, 99 C, 100 D), 4 cases of grade-5 toxicity have been reported (2 A, 1 B, 1 D): 3 deaths due to infection, 1 death coded neurocortical. Grade-4 toxicities have been reported for 29 patients (5 A, 7 B, 11 C, 6 D). Thus, 33 (8%) of the 399 eligible noncancelled patients with nonhematologic toxicity data experienced grade 4-5 toxicity; the percentages by treatment arm are 7.1%, 7.8%, 11.1%, and 7.0% for Arms A-D, respectively. Study Status: Study data have been cleaned, and the final analysis is in progress. Additional Information: The first report of the results of this trial was presented as a platform presentation at 2001 ASCO. The abstract is #202 in the ASCO Proceedings, Vol. 20: Phase III Trial of BCNU plus Cisplatin (CDDP) versus BCNU alone, and Standard Radiation Therapy (SRT) versus Accelerated Radiation Therapy (ART) in Glioblastoma (GBM) Patients (Pts): NCCTG/SWOG Results. JC Buckner, JC Michalak, PJ Schomberg, GV Burton, HM Sandler, TL Cascino, RB Hawkins, BW Scheithauer, JR O'Fallon. NCCTG Committee Page 3 of 8

11 Accrual Table: NCCTG Status Report for Study April 2002 Randomizing Membership Total Entered Ann Arbor 6 Bismarck 11 Carle 14 Cedar Rapids 10 Des Moines 18 Duluth 20 Fargo 12 Geisinger 15 Grand Forks 6 Mayo 46 Mo Valley 13 Ochsner 5 Peoria 15 Phoenix 1 Rapid City 5 Scottsdale 4 Sioux City 12 Sioux Falls 6 St. Cloud 11 Toledo 21 Total Membership Accrual 251 Randomizing Group Total Entered NCCTG 251 SWOG 200 Total Group Accrual 451 NCCTG Committee Page 4 of 8

12 NCCTG Status Report for Study April 2002 Baseline Characteristics Table: Characteristics Arm A Arm B Arm C Arm D Age Group < > Corticosteroids at entry Missing Yes No Extent of Resection BIOPSY SUBTOTAL RESECTION GROSS TOTAL RESECTION Family history brain tumor Missing Yes No Gender f m Histology PURE ASTROCYTOMA GLIOSARCOMA Performance Score Race Asian Black Hispanic Native Americian Native Hawaiian or Other Pacific Islande Other White NCCTG Committee Page 5 of 8

13 NCCTG Status Report for Study April 2002 Adverse Event Table: Arm A Evaluable Patients: 98 Arm B Evaluable Patients: 102 Arm C Evaluable Patients: 99 Arm D Evaluable Patients: 100 Body System Adverse Event A R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % Auditory/Hearing HEARING LOSS A B C D Constitutional Symptoms ANOREXIA A B C D LETHARGIC A B C D Dermatology/Skin ALOPECIA A B C D DERMATITIS A B C D SKIN REACTION A B C D Gastrointestinal CONSTIPATION A B C D DIARRHEA A B C D NAUSEA A B NCCTG Committee Page 6 of 8

14 NCCTG Status Report for Study April 2002 Body System Adverse Event A R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % C D STOMATATIS A B C D VOMITING A B C D Infection/Febrile Neutropenia INFECTION A B C D Neurology NEUROSENSORY A B C D NEURO CORTICAL A B C D NEURO VISION A B C D SEIZURES A B C D Pain HEADACHE A B C D Pulmonary PULMONARY A B C D Other OTHER A NCCTG Committee Page 7 of 8

15 NCCTG Status Report for Study April 2002 Body System Adverse Event A R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % B C D Maximum Toxicity A B C D NCCTG Committee Page 8 of 8

16 NCCTG Status Report for Study April 2002 Phase II Trial of Chemotherapy Plus Radiotherapy for Management of Primary Central Nervous System Non-Hodgkin's Lymphoma (PL) Purpose of Study: 1) To assess the effectiveness of CHOD + BVAM + WBRT in producing response in PL. 2) To assess toxicities associated with the use of CHOD + BVAM + WBRT. 3) To assess the survival of patients with combined modality therapy in PL. 4) To investigate the frequency of systemic involvement at follow-up (patterns of failure). 5) To identify factors that appear to be associated with outcome. Study Chairs: Brian P. O'Neill M.D. Ferdinand K. Addo M.D. Data Monitor: Butch K. Kvittem Statistician: Judith R. O'Fallon Ph.D. Nurse Resource: Gwen Finck R.N. Status: 07/25/ /08/ /18/ /27/2000 Activated Temp. Closed Reopened Perm. Closed Projected Number of Patients: 35 Excluded: None Final Accrual: 36 Stratification Schema: None Register CHOD BVAM WBRT Treating Schedule: Arm Agent Dose Route Days Freq * CTX 750 mg/m2 IV 1 Not repeated * ADR 50 mg/m2 IV 1 Not repeated * VCR 1.4 mg/m2 IV 1 Not repeated * DXM 4 mg Orally Q.I.D. 1-5 Not repeated # BCNU 100 mg/m2 IV 8 In 6 wks (wk 8) # VCR 1.4 mg/m2 IV 15 Every 2 wks X 5 # ARA-C 3 gm/m2 IV 16 Every 2 wks X 5 # MTX 1.5 gm/m2 IV 15 Every 2 wks X 5 NCCTG Committee Page 1 of 5

17 NCCTG Status Report for Study April 2002 Arm Dose Days FX/Day FX/Size # FX RT Length CGY M-F CGY /2 wks CGY M-F CGY /2 wks Chemotherapy * CHOD Rx Cycle # BVAM Cycles - Begin 1 wk after starting CHOD (day 8) Radiation Therapy - Begin RT 2 wks after finishing BVAM or if PROG dur >=10 days after last MTX infusion + <CR tumor response - CR tumor response Study Design: This trial has an initial stage of safety monitoring followed by a conventional two-stage design. Accrual was suspended after the first 5 patients were entered onto the study. If any unacceptable toxicities had been observed among these 5 patients, the study would have been closed. However, since no unacceptable toxicities were observed among these 5 patients, an additional 12 patients were entered. If 7 or fewer responses were observed in these first 17 patients, the study would have been closed, and the therapy would have been considered insufficiently active; if all 17 patients responded, the study could have been closed, and the therapy could be considered sufficiently active; if 8 to 16 patients responded, accrual would be reopened for the entry of a second batch of 18 patients; and final judgment regarding the activity of the therapy would be based on the responses seen in all 35 patients. Accrual: This study was opened on 7/25/95, and the first patient was enrolled one month later. Five cases were entered in the first six months, and the study was temporarily closed for toxicity monitoring on 3/8/96. The study was reopened on 6/8/96, and ECOG joined the study on 2/19/ 98. On 9/27/00 accrual was terminated after a total of 36 patients had been enrolled, 30 from 14 NCCTG memberships, the remaining 6 from 5 ECOG memberships. Accrual by membership is summarized in the Accrual Table below. Patient Characteristics: The Baseline Characteristics Table below summarizes several key characteristics of the 36 patients. The 19 men and 17 women (47%) ranged in age from 34 to 69 years old, with a median age of 60.5 years. Two (6%) are classified as minorities. Available Information: As of 2/15/02, 6 patients (17%) were still alive on study, 7 (19%) were alive off study, and 23 (64%) had died. Progressions had been recorded for 21 (58%). Thirtyfive patients (97%) were evaluable for response and toxicity. NCCTG Committee Page 2 of 5

18 NCCTG Status Report for Study April 2002 Adverse Events: The Adverse Events Table below summarizes the available adverse events data. Hematologic: With hematologic data available for 33 patients, 6 (18%) have had grade-4 leukopenia (WBC nadir <1.0), and one (3%) had grade- thrombocytopenia (PLT nadir <10). Grade-3 leukopenia (WBC nadir ) and grade-3 thrombocytopenia (PLT nadir 10-49) were reported for 18 (55%) and 8 (24%) patients, respectively. Nonhematologic: With nonhematologic toxicity data available for 35 patients, no grade-5 toxicities have been seen, but 4 grade-4 adverse events (sepsis syndrome, neurocortical, mucositis, seizures) have been reported. The patient with sepsis syndrome went off study and died a month later. Study Status: Closed to accrual on 9/27/00. Final analysis is in progress. Additional Information: The following abstract was submitted to ASCO Accrual Table: Randomizing Membership Total Entered Carle 1 Cedar Rapids 1 Des Moines 3 Duluth 1 Grand Forks 1 Mayo 10 Mo Valley 1 Peoria 3 Scottsdale 2 Sioux City 1 Sioux Falls 1 St. Cloud 3 Toledo 1 Wichita 1 Total Membership Accrual 30 Randomizing Group Total Entered NCCTG 30 ECOG 6 Total Group Accrual 36 NCCTG Committee Page 3 of 5

19 NCCTG Status Report for Study April 2002 Baseline Characteristics Table: Arm Characteristics A Gender f 17 m 19 Race Black 1 Native Americian 1 White 34 NCCTG Committee Page 4 of 5

20 NCCTG Status Report for Study April 2002 Adverse Event Table: Arm A Evaluable Patients: 35 Body System Adverse Event A R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % Constitutional Symptoms ANOREXIA A LETHARGIC A Dermatology/Skin ALOPECIA A DERMATITIS A Gastrointestinal CONSTIPATION A DIARRHEA A NAUSEA A STOMATATIS A VOMITING A MUCOSITIS A Neurology NEUROSENSORY A NEUROMOTOR A NEUROCEREBELLAR A NEURO CORTICAL A NEURO VISION A SEIZURES A Pain HEADACHE A Other OTHER A Maximum Toxicity A NCCTG Committee Page 5 of 5

21 Abstract The optimal treatment for PL is still unsettled. Current therapies extend survival but do not increase the cure rate. Furthermore, neurotoxicity remains a formidable concern. Methods. We conducted a Phase II trial in newly diagnosed biopsy-proven PL to assess the efficacy and toxicity of combined cyclophosphamide, adriamycin, vincristine, dexamethasone, BCNU, cytosine arabinoside and methotrexate followed by 30.6 Gy whole brain irradiation (WBRT) if complete response (CR) or 50.4 Gy WBRT if less than CR, both given at 1.8 Gy daily fractions. The primary efficacy endpoint was one-year survival. Patient entry was capped at age 70 years. Results. All 36 enrolled patients (19 men, 17 women) were eligible. Their median age was 60.5 years (range years). 33 patients (94%) had large cell histology; 30 (83%) had baseline ECOG performance scores of 0-1; 15 had measurable disease, and 19 had evaluable disease. Currently, 35 patients are eligible for response; 21 patients have progressed, and 23 have died. Of the 13 living patients, 7 are off study. Median survival is 66.3 weeks, and median time to progression is 46.4 weeks. Best response was CR in 9 patients and immediate progression in 7. 4 patients had grade 4 toxicity including 1 with life threatening sepsis syndrome. Conclusions. This regimen did not improve the survival of our PL patients. Further research into causation is needed in order to develop pathogenesis-based prevention and treatment strategies.

22 NCCTG Status Report for Study April 2002 Diagnostic and Prognostic Markers in Anaplastic Astrocytoma and Anaplastic Oligoastrocytoma Purpose of Study: 1) To evaluate diagnostic and prognostic relevance of alterations of specific chromosomes and chromosomal regions using PCR analysis of microsatellite repeats and FISH. 2) To evaluate diagnostic and prognostic relevance of DNA ploidy by flow cytometric analysis and compare this with ploidy determinations by FISH. 3) To assess diagnostic and prognostic relevance of various markers of cellular proliferation and cellular function Study Chairs: Jan C. Buckner M.D. Paul L. Schaefer M.D. Data Monitor: Helen J Tollefson Statistician: Judith R. O'Fallon Ph.D. Nurse Resource: Status: 11/28/1995 Activated Projected Number of Patients: Excluded: None Final Accrual: NA Stratification Schema: None PCR, FISH, flow cytometry & immunohistochemical determinations performed in laboratory of Dr. R. B. Jenkins & the Mayo Cancer Center Pathology Laboratory Treating Schedule: No treatment information Study Design: Original Design: This prognostic factors study was originally designed to evaluate a battery of tumor markers in patients with grade-3 astrocytomas (AA) or high-grade oligoastrocytomas (AOA) who were enrolled in 3 NCCTG randomized clinical trials in newlydiagnosed high-grade gliomas ( , , ). The dataset would consist of the prospectively-collected clinical data from these 3 trials together with associated baseline tumor marker data measured on paraffin-embedded tissue collected from each of the clinical trials participants at the time s/he enrolled in the trial. During 1997, the eligible patients were identified, and paraffin blocks were collected from 108 of them. Each block was audited to determine if tumor was present. Specimens from 85 patients were found suitable for further marker analysis. Sections from these blocks were cut, and flow cytometry, immunohistochemical staining for PCNA, MIB-1, and p53, and image cytometry analysis of DNA ploidy were performed. During 1998, a comprehensive FISH analysis of these specimens and screening for PTEN gene mutations was done. NCCTG Committee Page 1 of 4

23 NCCTG Status Report for Study April 2002 While the blocks were being collected from the NCCTG member institutions, several new potential markers that could be measured in paraffin-fixed tissue were identified by participants in the NCI-sponsored Glioma Markers Network (GMN) in which Mayo participated. Moreover, the study team realized that, as written, protocol did not require the accrual of tumors from patients with GBM, i.e., grade-4 astrocytoma. In retrospect, this was an oversight because this group of patients could provide comparable information about the incidence of marker anomalies and the survival of patients with and without specific marker alterations. REVISED DESIGN: Consequently, the protocol was rewritten to accrue paraffin-embedded tissue specimens from patients with newly-diagnosed GBM who were enrolled in any of the Mayo/ NCCTG high-grade glioma clinical trials. To enhance the likelihood of finding the most prognostic markers associated with this disease, NCCTG Translational Research Committee and the GMN participants jointly agreed to include in the univariate and multivariate analyses to be done in this protocol those promising GMN markers that were approved by both of them, and appendices justifying 4 new markers were incorporated. The revised protocol was approved by member IRBs during Accrual: By the cutoff date for this report (2/15/02), tissue blocks had been received for 328 patients from 17 memberships who were enrolled in 13 Mayo/NCCTG trials for newly-diagnosed high-grade gliomas. They comprise 18% of all patients enrolled in those 13 trials. See the Accrual Table and the Trials Table below. Patient Characteristics: The 328 patients for whom blocks have been submitted consist of 116 women (35%) and 212 men. Five are classified as ethnic minorities. The tissues from these 328 patients are currently classified as 109 AAs, 27 AOAs, 187 GBMs, 2 gliosarcomas, and 3 highgrade oligos. Available Information: Virtually complete and up-to-date clinical and follow-up data are available for all patients who participated in any of 13 Mayo/NCCTG clinical trials in newly-diagnosed high-grade glioma. Deaths have now been recorded for 268 (81%) or the 328 patients on this study. Study Status: Evaluation of the various markers discussed above on the available tissue is nearly complete, and preliminary analyses have been done. The following reports of the results have been presented. * Jenkins RB, Perry A, O'Fallon JR, Scheithauer BW, Smith S, Hill E, Sebo TJ, Buckner JC: An evaluation of DNA content and markers of cellular proliferation in a cohort of uniformlytreated patients with anaplastic astrocytoma. J Neuro-Oncol 19:100 (Abstract O-7), NCCTG Committee Page 2 of 4

24 NCCTG Status Report for Study April 2002 * Perry A, Jenkins RB, O'Fallon JR, Mahoney MR, Scheithauer BW,Smith SM, Hill EM, Sebo TJ, Buckner JC: Clinicopathologic study of 66 uniformly treated anaplastic astrocytomas: An analysis of DNA content (ploidy), cellular proliferation, and p53 expression. Society for Neuro-Oncology, * Perry A, Jenkins RB, O'Fallon JR, Schaefer PL, Kimmel DW, Mahoney MR, Scheithauer BW, Smith SM, Hill EM, Sebo TJ, Levitt R, Krook J, Tschetter LK, Morton RF, Buckner JC: Clinicopathologic study of 85 similarly treated patients with anaplastic astrocytic tumors: An analysis of DNA content (ploidy), cellular proliferation, and p53 expression. Cancer 86: , * Imoto I, Huntley B, Borell T, O'Fallon JR, Mahoney MR, Hosek SM, Schaefer P, Scheithauer BW, James CD, Buckner JC, Jenkins RB: Prognostic value of EGFR amplification, PTEN mutation, and TP53 mutation in anaplastic astrocytomas. Neuro-Oncology 1:326(A94), * Kuriyama H, Lamborn KR, O'Fallon J, Iturria N, Kuriyama N, Sebo TJ Schaefer PL, Buckner JC, Jenkins RB, Israel MA: Prognostic significance of an apoptosis/proliferation ratio for patients with glioblastoma multiforme. Neuro-Oncology 2: 276 (A126),2000. * Smith JS, Tachibana I, Passe SM, Huntley BK, Borell TJ, Iturria N, O'Fallon JR, Schaefer PL, Scheithauer BW, James CD, Buckner JC, Jenkins RB: PTEN tumor suppressor gene mutation and EGFR amplification and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. (put JNCI reference in here) * Buckner JC, Smith JS, Nelson DF, Zenk D, Shevlin BE, Hammack JE, Borell TJ, O'Fallon JR, Scheithauer BW, Jenkins RB: Phase II trial o procarbazine CCNU, and vincristine (PCV) as initial therpay in patients with low-grade oligodendroglioma or oligoastrocytoma: Efficacy results and associations with chromosome 1p and 19q loss. (ASCO, 1999 Meeting). NCCTG Committee Page 3 of 4

25 Accrual Table: NCCTG Status Report for Study April 2002 Randomizing Membership Total Entered Past 6 Months Past 12 Months Bismarck Carle Cedar Rapids Des Moines Duluth Fargo Grand Forks Mayo Mo Valley Ochsner Peoria Rapid City Scottsdale Sioux City Sioux Falls St. Cloud Toledo Total Membership Accrual NCCTG Committee Page 4 of 4

26 NCCTG Status Report for Study April 2002 Diagnostic and Prognostic Markers in Low-Grade Glioma Purpose of Study: 1) To evaluate diagnostic and prognostic relevance of alterations of specific chromosomes & chromosomal regions using PCR analysis of microsatellite repeats and FISH. 2) To evaluate diagnostic and prognostic relevance of DNA ploidy by flow cytometric analysis and compare this with ploidy determinations by FISH. 3) To assess diagnostic & prognostic relevance of various markers of cellular proliferation and cellular function. Study Chairs: Jan C. Buckner M.D. Robert Arusell M.D. Data Monitor: Helen J Tollefson Statistician: Judith R. O'Fallon Ph.D. Nurse Resource: Status: 12/01/1995 Activated Projected Number of Patients: Excluded: 1 Final Accrual: NA Stratification Schema: None PCR, FISH, flow cytometry, & immunohistochemical determinations performed in the laboratory of Dr. R. B. Jenkins & the Mayo Cancer Center Pathology Laboratory Study Design: Original Design: This prognostic factors study was designed to evaluate a battery of tumor markers in patients with low-grade astrocytomas, oligodendrogliomas, or mixed oligoastrocytomas who were enrolled in 2 clinical trials for newly-diagnosed low-grade gliomas, i.e., the first NCCTG-led intergroup phase-iii trial in this population ( ) and a thenongoing Mayo/NCCTG phase-ii trial ( ). The dataset will consist of the prospectivelycollected clinical data from these 2 trials together with associated baseline tumor marker data measured on paraffin-embedded tissue collected from each of the clinical trials participants at the time s/he enrolled in the trial. While the blocks were being collected from the NCCTG member institutions, several new potential markers that could be measured in paraffin-fixed tissue were identified by participants in the NCI-sponsored Glioma Markers Network (GMN) to which Mayo belongs. Revised Design: In order to enhance the likelihood of finding the most prognostic markers associated with this disease, the NCCTG Translational Research Committee and the GMN participants jointly agreed to include in the univariate and multivariate analyses to be done in this protocol those promising GMN markers that were approved by both of them. Appendices justifying the new markers were added to the original protocol, and the revised protocol was approved by the NCCTG IRBs during NCCTG Committee Page 1 of 3

27 NCCTG Status Report for Study April 2002 Accrual: This study was activated by NCCTG on 12/1/95. By the cutoff date for this report (2/ 15/02), 134 patients from 12 memberships had been registered for this study, as shown in the Accrual Table. These comprise 49% of the 275 patients enrolled in these 2 trials (232 in , 43 in ). Patient Characteristics: The 134 patients registered for this study consist of 54 women (40%) and 80 men. One is classified as an ethnic minority. Between registration in this study and submission of pathology materials, one patient cancelled out of Upon pathology review, 4 patients have been declared ineligible. Two patients were declared ineligible after their tissues were reclassified as high-grade gliomas (1 AA, 1 AOA). The third patient was classified as a ganglioma. The specimen of the fourth patient could not be definitively classified as astrocytoma, oligoastrocytoma, or oligodendroglioma. One eligible patient with astrocytoma was not graded by the pathologist due to concern about the representativeness of the biopsy sample. The histologic classifications for the remaining 128 tissues are summarized in the Tissue Block Classification Table. Available Information: Virtually complete and up-to-date clinical and follow-up data are available for all patients who participated in either of the 2 NCCTG clinical trials in newly-diagnosed low-grade glioma. Deaths have now been recorded for 63 (47%) of the patients registered to this study. Study Status: Acquisition of tissue blocks from patients enrolled in the recently-closed lowgrade clinical trial continues. With only 63 deaths documented in this prognostic factors study % of the 129 so far recorded in the 2 low-grade glioma trials (119 in , 10 in ) --, definitive analysis must be postponed. * Preliminary analysis of specimens from patients participating in NCCTG (Phase II Study of Preirradiation PCV Chemotherapy in Patients with Supratentorial Low-Grade Gliomas) suggested that 1p and 19q loss are associated with oligodendroglioma but not oligoastrocytoma. Futhermore, patients with 1p and 19q loss rarely had p53 abnormalities, whereas those without 1p or 19q loss did have p53 mutations. Response to PCV chemotherapy was not associated with 1p or 19q loss. (Buckner JC, Smith JS, Nelson DR, Zenk D, Shevlin BE, Hammack JE, Borell TJ, O'Fallon JR, Scheithauer BW, Jenkins RB: Phas II Trial of Procarbazine, CCNU, and Vincristine (PCV) as Initial Therapy in Patients with Low-Grade Oligodendrogliomas or Oligoastrocytoma: Efficacy Results and Associations with Chromosome 1p and 19q Loss. Proc Amer Soc Clin Oncol 18:140a (A536), 1999, and unpublished data.) NCCTG Committee Page 2 of 3

28 Accrual Table: NCCTG Status Report for Study April 2002 Randomizing Membership Total Entered Ann Arbor 1 Bismarck 4 Carle 4 Cedar Rapids 1 Des Moines 13 Duluth 1 Fargo 17 Grand Forks 3 Mayo 84 Ochsner 2 Sioux City 3 Sioux Falls 2 Total Membership Accrual 135 Histologic Classification Table Cell Type Grade 1 2 Total Astrocytoma Oligoastro Oligo Total = NCCTG Committee Page 3 of 3

29 NCCTG Status Report for Study April 2002 Clinical Significance of Histologic Typing of High-Grade Glioma Purpose of Study: 1) To estimate (describe) time-to-progression & time-to-death distributions for selected cell types of high-grade tumors. 2) To identify clinical and histologic characteristics associated with time-toprogression and/or time-to-death. 3) To identify prognostic groups based on clinical and histologic characteristics, ones possibly more predictive of survival than clinical or morphologic parameters alone. Study Chairs: Jan C. Buckner M.D. Data Monitor: Helen J Tollefson Statistician: Judith R. O'Fallon Ph.D. Nurse Resource: Status: 11/28/ /18/1996 Activated Perm. Closed Projected Number of Patients: 950 Excluded: None Final Accrual: 827 Stratification Schema: None Slides revewed by Dr. Scheithauer according to WHO criteria. Data entered into neuropathology database. Treating Schedule: No treatment information Study Design: ORIGINAL DESIGN: This prognostic factors study was designed to identify clinical and histologic characteristics associated with time-to-progression and time-to-death in patients with newly-diagnosed high-grade glioma who enrolled in the first 3 NCCTG high-grade glioma phase-3 clinical trials ( , , ). The dataset consisted of the prospectively-collected clinical data from these 3 trials together with associated baseline pathology data measured on paraffin-embedded tissue collected from each of the clinical trials participants at the time s/he enrolled in the trial. The primary hypotheses to be tested were: * The following morphologic criteria impart an inferior prognosis when compared with pure fibrillary astrocytoma of the same grade: gemistocytic, small cell, giant cell, or sarcomatous elements. * Tumors which contain oligodendroglial features are associated with superior survival when compared with pure fibrillary astrocytoma of the same grade. * Small cell and sarcomatoid features are associated with increased risk of clinically apparent leptomeningeal dissemination compared with pure fibrillary astrocytoma. NCCTG Committee Page 1 of 5

30 NCCTG Status Report for Study April 2002 Patient histories were reviewed to ascertain whether or not meningeal dissemination was documented antemortem. Johns Hopkins neuropathologist Peter Burger reviewed all cases with morphologic freatures described above as well as a subset of pure fibrillary astrocytomas, grade 3 and 4, as suggested by NCI. REVISED DESIGN: The dataset created for the original study proved to be so useful that it was expanded into a Neuropathology Databank, which includes pathology reviews by Bernd Scheithauer of the slides submitted for all the patients enrolled in MCCC/NCCTG glioma trials, those for recurrent and low-grade glioma as well as those for subsequent high-grade glioma trials. Accrual: ORIGINAL STUDY: The original Clinical Significance of Histologic Typing in High-Grade Glioma study was activated by NCCTG on 11/28/95 and closed to accrual on 10/18/ 96. Approximately 30 of the 950 participants in the 3 designated trials are known to have missing tissue. Tissue slides for 827 participants (90% of the remaining 920) were submitted by 19 memberships for re-review; these contributions were tabulated by membership in the 1998 Meeting Book. All available tissue samples have now been reviewed. NEUROPATHOLOGY DATABANK: On 3/11/02, a total of 2448 tumors are registered in the Neuropathology Databank. Reasonably complete tissue information is available for 2127 newly-diagnosed gliomas and 256 recurrent gliomas. In addition, there are 24 primaries and 16 recurrences with nondiagnostic tissue, lost slides, celltypes that were either ineligible for their parent protocol or that the Databank was not designed to collect (ependymoma, ganglioma, neurocytoma) or had one or more key pathology data items missing, and slides for 25 registered tumors are missing altogether. Currently, there are 2 patients with 2 primary tumors each, 11 patients with 2-3 recurrent tumors each, and 191 patients with both primary and recurrent tumor tissue in the Databank. Tables 1 and 2 summarize, respectively, celltype x grade and clinical trial participation separately for newly-diagnosed vs recurrent cases. Patient Characteristics: ORIGINAL STUDY: The 827 patients consisted of 337 women (41%) and 490 men. Six were classified as ethnic minorities. NEUROPATHOLOGY DATABANK: Patient data are available in the clinical trials research files but are not yet summarized in the Neuropathology Databank. Available Information: Up-to-date clinical and follow-up data are available in the clinical trials research files for nearly all patients. Possible exceptions are those who were classified as ineligible for the clinical trials in which they were registered. NCCTG Committee Page 2 of 5

31 NCCTG Status Report for Study April 2002 Study Status: * Dr. Peter Burger visited the Research Base on January 8-10, 1997, to review, in blinded fashion, slides for 150 patients with tissue officially classified as high-grade oligoastrocytoma (N=59), grade-3 astrocytoma (N=59), gliosarcoma (N=16), and a matched set of grade-4 astrocytomas (N=16). * A workshop to permit NCCTG pathologists to review, in blinded fashion, a representative subset of the 150 slides classified by both Bernd Scheithauer and Peter Burger was conducted by the NCCTG Pathology Committee at its 1997 Fall Meeting. The pathology forms completed by the workshop participants were keyed into the computer, and summary analyses were presented and discussed at the 1998 Spring Meeting as an educational enterprise. * An analysis of the gliosarcoma subset was presented at the 1997 AACR meeting; the abstract was printed in the 1997 (Spring) Meeting Book. The manuscript has been published: Galanis E, Buckner JC, Dinapoli RP, Scheithauer BW, Jenkins RB, Wang C-H, O'Fallon JR, Farr G: Clinical outcome of gliosarcoma compared with glioblastoma multiforme: North Central Cancer Treatment Group results. Journal of Neurosurgery 89: , * Comparison of anaplastic astrocytoma vs. grade-3 oligoastrocytoma/glioblastoma vs. grade-4 oligoastrocytoma was presented at the 1997 meeting of the Society for Neuro-Oncology; the abstract was printed in the 1998 Meeting Book [Buckner JB, Scheithauer BW, O'Fallon JR, Wang C-H, Dinapoli RP, Schomberg PJ, Farr G, Schaefe P: Superior survival of patients with anaplastic oligoastrocytoma (AOA) vs anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM). The manuscript is nearing completion. * The following abstract has been accepted for oral presentation at the 2002 ASCO Annual Meeting and given the ASCO Merit Award: Ravi D. Rao, Bernd Scheithauer, Caterina Giannini, Nancy Iturria, Judith O'Fallon, Paul Schaefer, Jan C. Buckner: Prognostic Significance of Histologic Subtyping in High Grade Astrocytoma: NCCTG Results. This abstract is presented below. * A second abstract has been accepted for poster/discussion presentation at the 2002 ASCO Annual Meeting: Jan C. Buckner, Bernd W. Scheithauer, Robert P. Dinapoli, Jenry J. Votava, Caterina Giannini, Nancy Iturria, Judith R. O'Fallon: Comparison of Mixed Anaplastic Oligoastrocytoma and High-Grade Astrocytoma in NCCTG Clinical Trials of High-Grade Glioma. This abstract is presented below. NCCTG Committee Page 3 of 5