Clinical trial NCT00200161
Conditions: Glioblastoma Gliomas
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2005-08-09; Completion date: 2017-05-04
Enrollment: 127 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patients have a newly diagnosed brain tumor called a malignant glioma and participate in the study to see if it is possible to increase the benefit of temozolomide when given after radiation. A recent study showed that patients with newly diagnosed glioblastoma lived longer when treated with both temozolomide and radiotherapy followed by 6 months of temozolomide than patients treated with radiotherapy alone. Patients will receive standard low dose temozolomide during radiation. After radiation, they will be randomized to receive either more intense temozolomide or continuous low dose temozolomide.

Detailed description:
This is a randomized phase II study that will test two different adjuvant temozolomide regimens in patients with newly diagnosed glioblastoma multiforme. The goal of this study is to identify a regimen that would be appropriate to bring to a phase III trial and compare to the standard dosing regimen of temozolomide recently reported by Stupp et al. in the New England Journal of Medicine. Secondary goals of this study include: prospective analysis of the prognostic impact of MGMT status and generation of preliminary data regarding this treatment strategy for other types of malignant glioma.

The decision regarding which treatment patients receive is made randomly. Neither them or their doctor can select which treatment the patient will receive. There is reason to believe that both of these doses may benefit treating your brain tumor. After 6 months of chemotherapy, and assuming the brain tumor has not shown any sign of growth, they will begin receiving cis-retinoic acid. Cis retinoic acid has been shown in one study to possibly prevent or delay tumor recurrence.

Arms: arm 1: Concurrent temozolomide and radiotherapy plus lose dose of temozolomide arm 2: Concurrent temozolomide and radiotherapy plus high dose of temozolomide
Interventions: intervention 1: Temozolomide intervention 2: Temozolomide
Intervention descriptions: intervention 1: Focal RT 6000 cGy/ Temozolomide 75 mg/m2 then Temozolomide 50mg/m2 will be given to patients on days 1-28 of each 28 day cycle. Maintenance cis-retinoic acid. This therapy will start at the completion of 6 cycles of adjuvant temozolomide in all patients who have had no clinical or radiographic evidence of tumor progression.Treatment will continue in 28 day cycles until tumor progression. intervention 2: Focal RT 6000 cGy/ Temozolomide 75 mg/m2 plus Temozolomide 150 mg/m2 will be given to patients on days 1-7 and 15-21 of each 28 day cycle. Maintenance cis-retinoic acid. This therapy will start at the completion of 6 cycles of adjuvant temozolomide in all patients who have had no clinical or radiographic evidence of tumor progression.Treatment will continue in 28 day cycles until tumor progression.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-079 A(17) 
Amended: 11/08/11 
 
 
 
 
 
 
 
A randomized phase II trial of concurrent temozolomide and radiotherapy followed by 
dose dense versus metronomic temozolomide and maintenance cis-retinoic acid for patients 
with newly diagnosed glioblastoma and other malignant gliomas. 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal 
Investigator/Department: 
Lisa DeAngelis, M.D. 
Neurology: Neurology 
Co-Principal 
Investigator(s)/Department: 
Elena Pentsova, M.D. 
Neurology: Neurology 
Investigator(s)/Department: 
Xi Chen, M. D. 
Igor Gavriolovic, M. D. 
Ingo Mellinghoff, M. D. 
Craig Nolan, M. D. 
Antonio Omuro, M. D. 
Thomas Kaley, M.D. 
Mariel Deutsch, M.D. 
Anna Delios, M.D. 
Iyavut Thaipisuttikul, M.D. 
Mary Welch, M.D. 
Jason Huse, M. D. 
Sasan Karimi, M. D. 
Kathy Panageas, DSc. 
Yoshiya Yamada, M.D. 
Kathryn Beal, M.D. 
Timothy Chan, M.D. 
Neurology: Neurology 
Neurology: Neurology 
Neurology: Neurology 
Neurology: Neurology 
Neurology: Neurology 
Neurology: Neurology 
Neurology: Neurology 
Neurology: Neurology 
Neurology: Neurology 
Neurology: Neurology 
Pathology: Surgical Pathology 
Radiology: Radiology 
Epidemiology and Biostatics: 
Biostatistics 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. New 
York, NY 10021 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-079 A(17) 
Amended: 11/08/11 
 
 
 
Consenting 
Professional(s)/Department: 
Xi Chen, M. D. 
Neurology: Neurology 
Lisa Deangelis, M. D. 
Neurology: Neurology 
Igor Gavriolovic, M. D. 
Neurology: Basking 
Ridge 
Ingo Mellinghoff, M. D. 
Neurology: Neurology 
Craig Nolan, M. D. 
Neurology: Commack 
Antonio Omuro, M. D. 
Neurology: Neurology 
Thomas Kaley, M.D. 
Neurology: Neurology 
Edward Avila, DO 
Neurology:Neurology 
Christian Grommes, M.D. 
Neurology: Neurology 
Elena Pentsova, M.D. 
Neurology: Neurology 
Patrick Morris, M.D. 
Neurology: Neurology 
Iyavut Thaipisuttikul, M.D. 
Neurology: Neurology 
Anna Delios, M.D. 
Neurology: Neurology 
Mary Welch, M.D. 
Neurology: Neurology 
See also section 15.0 
Participating Institutions 
Columbia University Medical 
Center 
Dana Farber Cancer Institute 
Site PIs 
Andrew B. Lassman, MD 
Lakshmi Nayak, MD 
Site Role 
Data Analysis 
Data Analysis 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. New 
York, NY 10021 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-079 A(17) 
Amended: 11/08/11 
 
 
 
A randomized phase II trial of concurrent temozolomide and radiotherapy followed by 
dose dense versus metronomic temozolomide and maintenance cis-retinoic acid for patients 
with newly diagnosed glioblastoma and other malignant gliomas. 
 
Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ………………………………………... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ………………………………………………. 3 
3.0 
BACKGROUND AND RATIONALE …………………………………………….......... 4 
4.0 
STUDY DESIGN ………………………………………………………………………... 8 
5.0 
THERAPEUTIC/ DIAGNOSTIC AGENTS ……………………………………………. 8 
6.0 
CRITERIA FOR PATIENT/ SUBJECT ELIGIBILITY………………………………… 9 
6.1 PATIENT/ SUBJECT INCLUSION CRITERIA …………………………………… 9 
6.2 PATIENT/ SUBJECT EXCLUSION CRITERIA …………………………………....9 
7.0 
RECRUITMENT PLAN ……………………………………………………………….. ..9 
8.0 
PRETREATMENT EVALUATION …………………………………………………... 10 
9.0 
TREATMENT/ INTERVENTION PLAN …………………………………………….. 11 
10.0 
EVALUATIONS DURING TREATMENT/ INTERVENTION ……………………...  12 
11.0 
TOXICITIES/ SIDE EFFECTS ………………………………………………………... 13 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/ OUTCOME ASSESSMENT …........ 13 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ………………………………………... 14 
14.0 
BIOSTATISTICS...…………………………………………………………………….. 14 
15.0 
SUBJECT REGISTRATION AND RANDOMIZATION PROCEDURES …………... 15 
15.1 PATIENT/SUBJECT REGISTRATION …………………………………………. 15 
15.2 RANDOMIZATION ……………………………………………………………… 17 
16.0 
DATA MANAGEMENT ISSUES ……………………………………………….......... 17 
16.1 QUALITY ASSURANCE ………………………………………………………... 17 
16.2 DATA SAFETY AND MONITORING ………………………………………….. 17 
17.0 
PROTECTION OF HUMAN SUBJECTS……………………………………………... 18 
18.0 
INFORMED CONSENT PROCEDURES ……………………………………….......... 19 
19.0 
REFERENCE(S)...…………………………………………………………………….... 19 
20.0 
APPENDICE(S) ………………………………………………………………………... 21 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a randomized phase II study that will test two different adjuvant temozolomide 
regimens in patients with newly diagnosed glioblastoma multiforme.  The goal of this 
study is to identify a regimen that would be appropriate to bring to a phase III trial and 
compare to the standard dosing regimen of temozolomide recently reported by Stupp et 
al. in the New England Journal of Medicine.  Secondary goals of this study include: 
prospective analysis of the prognostic impact of MGMT status and generation of 
preliminary data regarding this treatment strategy for other types of malignant glioma. 
 
Focal RT 6000 cGy/ Temozolomide 75 mg/m2 
 
 
 
 
 
 
 
 
Randomize 
 
 
 
 
 
 
 
 
Metronomic TMZ 50 mg/ m2/ d -or- dose dense TMZ 150 mg/m2 days 
1-7, 15-21 
 
 
 
 
 
 
 
 
Maintenance CIS Retinoic Acid 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary objective: To determine the overall survival of patients with newly diagnosed 
glioblastoma multiforme treated with concurrent temozolomide and radiotherapy 
followed by dose dense or metronomic dosing of temozolomide and maintenance cis- 
retinoic acid. 


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Secondary objectives: 
1.  Progression free survival 
2.  To evaluate the prognostic impact of methylated MGMT status. 
3.  To collect preliminary data on the efficacy of this regimen and impact of MGMT 
status in other malignant glioma subtypes. 
 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 Background 
 
The treatment of recurrent malignant gliomas represents a therapeutic challenge.  Even 
with maximum treatment at initial diagnosis, malignant gliomas have a dismal prognosis. 
Standard management is optimal surgical resection followed by involved field 
radiotherapy.  Historically, the role of chemotherapy has been controversial since median 
survival is not improved although a minority of patients may have prolonged survival. A 
randomized clinical trial failed to show any benefit (Medical research council brain tumor 
working party, 2001), but a prior meta-analysis of published randomized trials 
demonstrated a modest survival benefit for patients receiving adjuvant chemotherapy 
following radiotherapy (Fine et al., 1993). 
 
Temozolomide is a relatively new oral alkylating agent that was developed for the 
treatment of malignant glioma.  Initially approved in the United States for the treatment 
of recurrent anaplastic astrocytoma, temozolomide has been observed to have activity in 
the adjuvant treatment of glioblastoma multiforme.1,2  Furthermore, preclinical studies 
demonstrated evidence of synergistic activity of temozolomide when given in 
conjunction with radiotherapy.  The promising results of a phase II study of concomitant 
and adjuvant temozolomide and radiotherapy in newly diagnosed patients led to a large 
international phase III study to confirm these results.3 The primary endpoint of this phase 
III study was to compare overall survival in newly diagnosed glioblastoma multiforme 
patients treated with radiotherapy alone versus concomitant temozolomide and 
radiotherapy followed by adjuvant temozolomide.  573 patients with newly diagnosed 
GBM at 85 institutions were randomized to receive either radiotherapy alone (n= 286) or 
concomitant and adjuvant temozolomide (n=287). Patients were stratified on the basis of 
age, performance status, treating institution, and extent of resection.  Patients treated with 
radiotherapy alone received 30 fractions of 200 cGy using standard conformal treatment 
planning.  The schedule of temozolomide used during radiotherapy (concomitant dosing) 
was 75mg/m2 daily including weekends (days when radiotherapy was not administered) 
for six weeks.  Adjuvant therapy began four weeks after completion of radiotherapy with 
the standard recommended dose of temozolomide: 150-200mg/m2/day, days 1-5; a 
maximum of six cycles were administered. 


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With a median follow up for surviving patients of more than two years, there was a 
statistically and clinically significant improvement in median (14.6 v. 12.1 months) and 
two year overall survival (26 v. 10%) for patients treated with concomitant and adjuvant 
temozolomide as compared with radiotherapy alone. Median progression free survival 
was also significantly improved in the concomitant treatment group (p<0.0001).  Of 
importance, the two treatment groups were well balanced for known prognostic variables 
and the treatment was well tolerated in both groups with no unexpected toxicity observed. 
No cases of Pneumocystis carinii pneumonia were reported. Ten percent or less of those 
patients receiving temozolomide developed grade 3 or higher myelosuppression or 
fatigue. This was the first prospective phase III study to definitively show that 
chemotherapy has a clear role in the treatment of glioblastoma multiforme.7 Previously, 
there was significant evidence that chemotherapy played an important role in the 
treatment of glioblastoma multiforme4; however, the lack of level I evidence may have 
dissuaded conservative practitioners from pursuing aggressive therapy. While the overall 
prognosis remains poor even with the addition of concomitant and adjuvant 
temozolomide, a significant proportion of patients remain alive at two years. 
 
A subset analysis of patients enrolled on the phase III trial found that benefit of 
concomitant and adjuvant temozolomide was maintained across most known prognostic 
variables.  Those patients with a poor performance status, or whose tumors were only 
biopsied, derived less benefit.  Subset analysis was also performed using the RTOG RPA 
classification5. Improvement in progression free survival was maintained in all relevant 
classes (classes III, IV, V).  Class III and IV patients treated with concomitant and 
adjuvant therapy maintained the survival benefit. Correlative tissue analysis of patients 
enrolled suggests that patients whose tumors have a methylated form of an excision 
repair enzyme, O-6-methylguanine-DNA methyltransferase (MGMT), are particularly 
likely to benefit from concomitant and adjuvant temozolomide.6,8  Patients with 
methylated MGMT had approximately a 50% chance of surviving for two years. 
Methylation functionally inactivates the MGMT which in the active form is known to 
result in resistance to alkylating agents.  This observation may be critical to the 
development of other successful therapeutic strategies to enhance chemosensitivity. 
MGMT analysis should be incorporated into prospective clinical trials of alkylating 
agents. 
 
Experimentally and in vivo, temozolomide is schedule dependent.9   Recent studies in 
recurrent malignant gliomas used 150-200 mg/m2/daily for 5-days in a 28-day cycle.1,2 
However, a phase-I study of low dose continuous temozolomide defined a maximum 
tolerated dose (MTD) at 75 mg/m2/day for 42-days in a 70-day cycle (Brock et al., 1998). 
This regimen provides 2.1 fold greater drug exposure over 4-weeks compared to the 
standard 200 mg/m2 dose with comparable toxicity.  There was no evidence of drug 
accumulation and furthermore, this extended schedule may deplete O(6)-alkyl guanine- 
DNA alkyl transferase (AGT) levels, a potential mechanism of drug resistance. This 
treatment schedule may have improved efficacy as a result of increased drug exposure 
and decreased drug resistance without having an increase in treatment related toxicity. 


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Other temozolomide schedules can also be used to increase the dose density or to deliver 
continuous drug without interruption, thereby exploiting successful chemotherapy dosing 
strategies used in other solid tumors. 
 
3.2 Rationale for the proposed study 
 
This study is an effort to build on the results of the recently presented 
EORTC/NCIC study demonstrating that concurrent temozolomide and 
radiotherapy followed by 6 months of adjuvant temozolomide can significantly 
extend the life and disease free survival of patients with glioblastoma multiforme. 
The proposed study will provide preliminary data regarding several important 
questions: 
 
Is it feasible and effective to increase the delivered dose of adjuvant temozolomide (dose 
dense chemotherapy)? 
 
The concept of dose dense chemotherapy was pioneered by Larry Norton, MD and 
others at MSKCC in an effort to improve outcomes of patients with metastatic and 
high risk breast cancer. In this model dose density (body size adjusted dose divided 
by unit time) seeks to improve the overall impact of therapy by decreasing the time 
between dosing intervals and thereby decreasing the regrowth of resistant tumor 
cells between cycles of chemotherapy.  This model can be easily applied to glioma by 
utilizing one of the alternate dosing regimens for temozolomide that delivers 
150mg/m2 daily for 7 days on 7 days off.  This schedule is well tolerated and 
effectively delivers more than twice the standard dosing regimen and decreases the 
interval between cycles from 23 days to 7 days.11 
 
Is it feasible and effective to deliver continuous low dose temozolomide without 
interruption (metronomic chemotherapy)? 
 
Metronomic chemotherapy (antiangiogenic scheduling) has been proposed as an alternate 
dosing schedule for conventional chemotherapy.  The theory is that the obligatory rest 
period in conventional chemotherapy permits the recovery of endothelial cells and that 
altering the dosing regimen to allow for continuous low dose exposure without 
myelosuppression  and other dose limiting side effects will prevent the repair and 
recovery of tumor endothelium.12-15  Therefore we will plan to administer temozolomide 
at 50mg/m2 daily without interruption to half of the patients enrolled on this trial and 
assess feasibility and efficacy.  This schedule was chosen because it can be administered 
in a continuous fashion in patients with recurrent glioma for as long as 2 years (personal 
communication, J. Perry, Toronto), all other schedules of temozolomide require 
interruption to recover from treatment related toxicity. 
 
Is it possible to improve the outcome of patients with unmethylated or active MGMT by 
the use of alternate dosing regimens that effectively deplete MGMT levels? 


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An important mechanism of resistance to alkylating agents is the presence of active repair 
enzymes such as MGMT.  In the study by Stupp et al. patients with methylated or 
inactive MGMT were retrospectively described as having the greatest benefit while 
patients with unmethylated or active MGMT had substantially less benefit from the 
addition of temozolomide.  However, patients with active MGMT still had a statistically 
significant benefit in terms of progression free survival and 2 year overall survival with 
the addition of temozolomide.  Both of the alternate dosing regimens that we will 
randomize patients to have been demonstrated to result in significant depletion of 
MGMT.16  Therefore, in theory either regimen may result in increased treatment 
sensitivity. 
 
Does maintenance therapy help to maintain remission? 
 
One of the down sides of administering a 6 month course of adjuvant therapy to 
patients with glioblastoma is the high risk of tumor recurrence.  As a result many 
patients and clinicians are uncomfortable truncating therapy after 6 months in a 
patient who is doing well.  There is some data to suggest that some sort of 
maintenance therapy may be effective and substantially less toxic than continuing 
myelosuppressive chemotherapy indefinitely. One such study found that high grade 
glioma patients with a complete remission treated with maintenance 13-cis retinoid 
acid maintained their remission for an average of 74 weeks after starting 
maintenance therapy.10  This promising result merits further prospective 
investigation. 
 
Is the EORTC/NCIC regimen beneficial for patients with other types of high grade 
gliomas? 
 
The definitive answer to the above question will require a prospective randomized 
trial.  However, given the relative scarcity of these patients and numerous 
competing trials a prospective randomized trial may not be feasible. We would 
propose allowing patients with other malignant gliomas to enroll in our trial to 
obtain preliminary data.  The sample size and statistical design/accrual goals will be 
built around the glioblastoma population, other tumor types would be accrued and 
reported descriptively as part of the whole and as a subset. 
 
MGMT Correlative study: 
 
We plan to prospectively assay available tissue for MGMT methylation status to see 
if our results correlate with disease control/patient outcome.  If so, this would 
support the retrospective observation of the EORTC/NCIC. 


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4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This will be a single institution randomized phase II study that will allow us to 
concurrently assess the efficacy and toxicity of two different schedules of adjuvant 
temozolomide.  The prospective analysis and stratification based on MGMT status will 
allow us to confirm the observation of the EORTC/NCIC study. 
 
4.2 
Intervention 
 
The goal of this study is to look at two alternative ways to enhance chemotherapy 
delivery for patients with newly diagnosed malignant glioma.  All patients will receive 
concurrent temozolomide and radiotherapy followed by one of 2 different adjuvant 
temozolomide regimens.  They will be randomized to these adjuvant regimens on the 
basis of tumor histology and KPS.  At the completion of 6 cycles all patients will receive 
maintenance cis-retinoic acid until tumor progression. 
 
 
 
4.3 Statistics 
 
A Simon mini-max two stage design will be used for each arm of the protocol. If either 
regimen shows a one year survival probability of 70% or greater (27 patients surviving at 
one year) then a phase III trial comparing this regimen to the regimen reported by Stupp 
et al. will be proposed. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Temozolomide is an oral cytotoxic alkylating agent which undergoes spontaneous 
conversion to MTIC, the active metabolite of dacarbazine, at physiologic pH.  It has 
demonstrated activity against malignant glioma. 
 
Temozolomide is manufactured by Schering Plough, Inc.  It is available as 5, 20, 100 and 
250 mg capsules.  The 20mg and 100mg capsules are projected to be stable for at least 30 
months when stored between 2 and 30C in amber glass bottles.  The 5mg and 250mg 
capsules are projected to be stable for at least 12 months under the same conditions. 
 
Commercially available drug supply will be used for this study. 
 
Cis-retinoic acid is an oral retinoid that is manufactured by Roche Pharmaceuticals, Inc. 
and supplied as 10, 20 and 40mg capsules. 
 
Commercially available drug will be used for this study. 


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6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
Any adult patient with a newly diagnosed malignant glioma with available tissue would 
be eligible to participate. 
 
6.1 
Subject Inclusion Criteria 
 
• Pathologic evidence of a malignant glioma. 
• Tissue block or unstained slides must be available for MGMT analysis. 
• Age 18-70 
• KPS > 50 
• Granulocyte count >1.5 X 109/L 
• Platelet count >99 X 109/L 
• SGOT < 2.5X upper limit of normal (ULN). 
• Serum creatinine < 2X ULN. 
• Bilirubin < 2X ULN. 
• All patients must sign written informed consent. 
 
6.2 
Subject Exclusion Criteria 
 
• Any prior chemotherapy, radiotherapy and biologic therapy for glioma. 
• Any prior experimental therapy for glioma. 
• Other concurrent active malignancy (with the exception of cervical carcinoma in 
situ or basal cell ca of the skin). 
• Serious medical or psychiatric illness that would in the opinion of the investigator 
would interfere with the prescribed treatment. 
• Pregnant or breast feeding women. 
• Refusal to use effective contraception. 
 
7.0 
RECRUITMENT PLAN 
Recruitment Plan 
Patients will be recruited from the Neurology and Neurosurgery clinics at Memorial Sloan 
Kettering Cancer Center.  All patients will be seen by a Neuro-oncology attending. All 
patients enrolled on the trial must sign written informed consent.  There are no gender or 
racial restrictions. 
 
8.0 
PRETREATMENT EVALUATION 
 
The following studies are required within two weeks prior to starting concurrent 
chemotherapy and radiotherapy: 
 
• Complete history and physical exam including neurologic exam. 


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• Height and weight. 
• CBC including WBC differential and platelet count. 
• Comprehensive chemistry panel. 
• Contrast enhanced MRI scan of the Brain* (this scan should ideally be performed 
within 72 hours of surgery and does not need to be repeated within the two weeks 
prior to treatment onset) 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 Concurrent temozolomide and radiotherapy 
 
This treatment should start within 6 weeks of surgical resection. 
 
Standard focal external beam radiotherapy will be delivered using conventional radiation 
planning (3D conformal).  The total dose should be approximately 6000 cGy (+/- 5%). 
Stereotactic boost is not allowed.  Patients may receive their radiotherapy at MSKCC or 
locally provided that treatment planning and summary is available. 
 
Temozolomide will be given at a dose of 75mg/m2 daily for the complete course of 
radiotherapy.  Patients will start temozolomide the night before they receive the first dose 
of radiotherapy and take the last dose on the final day of radiotherapy.  Patients will dose 
on weekends and holidays when radiotherapy is not scheduled.  Supportive anti emetic 
therapy will be prescribed per institutional guidelines or at the discretion of the treating 
physician. 
 
9.2 Randomized adjuvant therapy 
 
This therapy will begin 2- 4 weeks after the completion of radiotherapy and will last for a 
total of 6 cycles (1 cycle = 28 days). Patients will be randomized to receive dose dense 
or metronomic temozolomide on the basis of histology and KPS. 
 
9.21 Dose dense temozolomide 
 
Temozolomide 150 mg/m2 will be given to patients on days 1-7 and 15-21 of each 28 day 
cycle. Supportive anti-emetic therapy will be prescribed per institutional guidelines or at 
the discretion of the treating physician.  Growth factors may be used to treat low blood 
counts but may not be given prophylactically. 
 
9.22 Metronomic temozolomide 
 
Temozolomide 50mg/m2 will be given to patients on days 1-28 of each 28 day cycle. 
Supportive anti-emetic therapy will be prescribed per institutional guidelines or at the 
discretion of the treating physician. Growth factors may be used to treat low blood 
counts but may not be given prophylactically. 


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9.3 Maintenance cis-retinoic acid. 
 
This therapy will start at the completion of 6 cycles of adjuvant temozolomide in all 
patients who have had no clinical or radiographic evidence of tumor progression. 
Treatment will continue in 28 day cycles until tumor progression. 
 
13-cis retinoic acid 100mg/m2 will be given on days 1-21 of each 28 day cycle. 
(Minor variations in dose are allowed given limited pill strength options).  On the 
first cycle patients may be given a titrated dose to evaluate tolerability. 
 
 
 
10.0  EVALUATION DURING TREATMENT/INTERVENTION 
During concurrent temozolomide and radiotherapy: 
• CBC every week. 
• Brief physical exam weekly by radiation oncology. 
• Contrast enhanced MRI (including perfusion) at the completion of radiotherapy 
and prior to initiation of adjuvant therapy – this will be considered a new baseline 
MRI and all patients may continue to adjuvant temozolomide. 
 
During adjuvant temozolomide: 
• CBC every week 
• Monthly exam 
• Contrast enhanced MRI (including perfusion) after every 2 cycles of therapy – 
patients with evidence of tumor progression as compared to the post radiotherapy 
MRI will be removed from the study. 
• Monthly comprehensive chemistry panel. 
 
During maintenance cis-retinoic acid: 
• Approximately monthly exam for 6 months then approximately every 2-3 months 
thereafter. 
• Monthly CBC, comprehensive chemistry panel and lipid panel. 
• Contrast enhanced MRI (including perfusion) after every 2-3 cycles of therapy - 
patients with evidence of tumor progression as compared to the post radiotherapy 
MRI will be removed from the study. 


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MGMT analysis: 
 
Unless MGMT analysis was already performed as part of routine care at MSKCC or an 
MSKCC designated laboratory, MGMT methylation analysis will be performed by real-time 
PCR using TaqMan machine via OncoMethylome Sciences SA. Ten paraffin slides (around 10 
micron), heated or baked (maybe less than 65C) per patient will be required. DNA will then be 
isolated and modified for real-time PCR on modified DNA. The final result will be the relative 
ratio of MGMT methylation / beta-actin as compared with positive control coming with the 
DNA modification kit. 
 
Greg Jones, (Project Coordinator NA) should be contacted before any shipment. Samples must 
arrive during business hours from Monday through Friday and shipped overnight to: 
 
OncoMethylome Sciences SA 
Attn: Cecilia Svensson 
Tour 5 GIGA nivau +3 
 
Avenue the l’Hôpital 11, 
 
4000 Liège Belgium 
 
Phone #: +32 4 364 20 70 
 
 
 
 
Contact information for Greg Jones: 
Phone: +1 919 281 09 80 
Fax: +1 919 281 09 81 
 
Email: greg.jones@oncomethylome.com 


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11.0 
TOXICITIES/SIDE EFFECTS 
 
Temozolomide: the most common grade 3 or 4 toxicities reported include: 
• <10%: nausea/vomiting, elevated liver enzymes, elevated BUN/Cr, constipation. 
• <5%: lymphopenia, thrombocytopenia, rash, headache, alopecia, fatigue. 
• 
<1%: lethargy. 
 
NCI CTC version 3.0 will be used to grade all toxicity. 
 
If hematologic toxicity grade 3 or higher occurs patients may be treated with appropriate 
growth factors.  If clinically indicated the dose of temozolomide may be reduced by 25%. 
 
If grade 3 or 4 treatment related non-hematologic toxicity occurs the dose of 
temozolomide may be reduced by 25%.  Temozolomide should be held until all related 
non hematologic toxicity has resolved to a grade 2 or lower. 
 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
All patients will have their tumor measurements recorded at baseline and at the time of 
each MRI scan.  Lesions must be measured in two dimensions.  The dose of gadolinium 
must be held constant from scan to scan. 
 
Because the first MRI obtained after radiotherapy often shows an increased pattern/area 
of enhancement of indeterminant significance this scan will not be used to assess 
response to therapy or to make a decision as to whether or not a patient remains on study. 
The first MRI after radiotherapy will be used as a new baseline scan for subsequent MRI 
assessments. 
 
Complete response (CR) is the total disappearance of all measurable contrast enhancing 
tumor on two MRIs separated by at least 4 weeks.  The patient must have no clinical 
neurologic deterioration or decrease in performance status.  The patient must be off 
dexamethasone. 
 
Partial response (PR) is at least a 50% reduction in the size of measurable contrast 
enhancement (the sum of the products of the greatest length and maximum width of all 
measurable lesions).  No lesion may progress and no new lesions may appear.  All PR 
should be confirmed by repeat MRI separated by at least 4 weeks.  The dose of 
dexamethasone must be the same or lower than at baseline. 
 
Stable disease (SD) exists when a patient fails to qualify for partial response or 
progressive disease. 


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Progressive disease (PD) is an increase of 25% or more in the size of any lesion or the 
appearance of a new site of tumor. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
If at anytime the patient develops progressive disease he/she will be taken off study and 
referred for alternative therapy. 
 
If at anytime the patient develops unacceptable toxicity he/she will be removed from 
study. 
 
If at anytime the patient is found to be ineligible for the protocol as designated in the 
section on Criteria for Patient/Subject Eligibility (i.e., a change in diagnosis), the patient 
will be removed from the study. 
 
14.0 
BIOSTATISTICS 
 
14.1 The primary goal of this study is to determine if either of the two regimens is 
appropriate to bring to a phase III study as the experimental arm in comparison to the 
regimen reported by Stupp et al.  To do this we will use overall survival as the primary 
endpoint for consistency. 
 
The primary objective of this study is to determine the overall survival of the two cohorts 
of patients randomized to either dose dense or metronomic dosing of temozolomide. 
Overall survival will be calculated from the date of study entry until death or date of last 
follow up using the Kaplan Meier product limit method.  Patients will be censored on the 
date of last follow up.  The primary endpoint is survival probability at 1 year. 
 
In this trial, we will utilize a Simon mini-max two-stage design for each cohort of 
glioblastoma patients, in which a 50% survival probability at one year is considered not 
promising, a 70% survival probability at one year is considered promising, and the 
probabilities of a type I error (falsely accepting a non-promising therapy) and type II 
error (falsely rejecting a promising therapy) are set at 0.10 and 0.10, respectively. In the 
first stage of this design, 23 patients will be accrued to each cohort.  If at least 12 patients 
are alive at one year among these 23 patients, then an additional 16 patients will be 
accrued to the second stage.   If 11 or less are alive of the 23 patients with one year 
follow-up then that cohort will be terminated and declared negative. At the end of the 
trial if 24 or more patients are alive at one year then the regimen would be considered 
worthy of further study.  This design yields at least a 0.90 probability of a negative result 
if the true survival probability is at least 50% and yields a 0.90 probability of a positive 
result if the true survival probability is 70%.  If both cohorts are considered promising 
with regard to the primary endpoint then the one with the higher one year survival 
probability will be considered for further evaluation in the phase III setting. 


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14.2 Secondary endpoints include progression-free survival defined as the date of study 
entry to the first scan that demonstrates tumor progression (please note that the MRI after 
completion of radiotherapy will be used as the baseline scan for response assessment). 
Frequency of toxicity will be tabulated according to the NCI Common Toxicity Criteria 
(version 3.0).   Methylation MGMT status will be assessed using real-time PCR.   A 
Fishers exact test will be used to compare one year survival by MGMT status 
(methylated/unmethylated) in order to observe any trends similar to that from the 
retrospective EORTC/NCIC. 
 
In addition, these regimens will be administered to forty patients with all other malignant 
glioma subtypes. Up to twenty patients in each arm will be accrued. Endpoints such as 
one-year survival probability, overall survival and progression-free survival will be 
computed in order to gain preliminary data for these other subtypes. 
 
The minimum anticipated sample size would be 66 patients (23 in each cohort plus 20 
patients with other malignant glioma subtypes.)  If both cohorts accrue patients to the 
second stage then a total of 118 evaluable patients will be accrued (39 in each cohort + 40 
patients with other malignant glioma subtypes). To ensure 118 evaluable patients, we will 
accrue 140 patients to guard against a 20% rate of ineligibility and patient drop out 
observed during an interim analysis.  Patients who withdraw consent or are found to be 
ineligible can be replaced.  The anticipated rate of accrual is 6 patients/month requiring 
12-18 months to complete the accrual to the trial. 
 
14.3 RANDOMIZATION: 
 
Patients will be randomized to dose dense temozolomide or metronomic temozolomide. 
After eligibility is established and immediately after consent is obtained, patients will be 
registered in the Protocol Participant Registration (PPR) system and randomized using 
the Clinical Research Database (CRDB), by calling the MSKCC PPR registry at 646- 
735-8000 between the hours of 8:30 am and 5:30 pm, Monday - Friday.  Randomization 
will be accomplished by the method of random permuted block, and patients will be 
stratified by KPS (<80 vs ≥ 80). 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
Research Participant Registration 
15.1      Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject 
Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 


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All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. The PPR fax numbers are (646) 735- 
0008 and (646) 735-0003. Registrations can be phoned in or faxed. The completed 
signature page of the written consent/verbal script and a completed Eligibility Checklist 
must be faxed to PPR. 
 
15.2   Randomization 
At registration, patients will be randomized to receive either Dose Dense Temozolomide 
or Metronomic Temozolomide.  Each group will receive 6 months of post radiation 
chemotherapy.  Randomization Codes will be generated by the Clinical Research 
Database (CRDB) in conjunction with the Department of Epidemiology and Biostatistics. 
 
 
16.0 
DATA  MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study.  The responsibilities of 
the RSA include project compliance, data collection, abstraction and entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and coordinate 
the activities of the protocol study team. 
 
The data collected for this study will be entered into a secure database.  Source 
documentation will be available to support the computerized patient record. 
 
16.1 
Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration data.  Routine data quality reports will be generated to assess 
missing data and inconsistencies.  Accrual rates and extext and accuracy of evaluations 
and follow-up will be monitored periodically throughout the study period and potential 
problems will be brought to the attention of the study team for discussion and action 
 
Random-sample data quality and protocol compliance audits will be conducted by the 
study team, at a minimum of two times per year, more frequently if indicated. 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer 
Center were approved by the National Cancer Institute in September 2001. The plans 
address the new policies set forth by the NCI in the document entitled “Policy of the 
National Cancer Institute for Data and Safety Monitoring of Clinical Trials” which can be 
found at: http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research. The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm 


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There are several different mechanisms by which clinical trials are monitored for data, 
safety and quality. There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and 
staff education on clinical research QA) and departmental procedures for quality control, 
plus there are two institutional committees that are responsible for monitoring the 
activities of our clinical trials programs. The committees: Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinical trials, report to the Center’s Research Council and 
Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for 
its level of risk and degree of monitoring required. Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be 
addressed and the monitoring procedures will be established at the time of protocol 
activation. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
17.1 Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form.  The use 
and disclosure of protected health information will be limited to the individuals described 
in the Research Authorization form.  A Research Authorization form must be completed 
by the Principal Investigator and approved by the IRB and Privacy Board. 
 
 
 
17.2 Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be 
submitted electronically to the SAE Office at sae@mskcc.org containing the following 
information: 
 
Fields populated from the CRDB: 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 


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• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following information: 
o A explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form 
 
The PI’s signature and the date it was signed are required on the completed report. 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that 
they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicating their consent to participate. This consent form 
meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
 
1.   The nature and objectives, potential risks and benefits of the intended study. 
2.   The length of study and the likely follow-up required. 
3.   Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive care 
for therapeutic studies.) 
4.   The name of the investigator(s) responsible for the protocol. 
5.   The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information. 
 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 


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19.0 
REFERENCE(s) 
 
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Olson J, Chang SM, O'Neill AM, Friedman AH, Bruner J, Yue N, Dugan M, Zaknoen S, Levin 
VA.  Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or 
anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group.  J Clin Oncol. 1999 
Sep;17(9):2762-71. 
 
2.  Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, 
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Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA.  A phase II study of temozolomide 
vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000 
Sep;83(5):588-93. 
 
3.  Stupp R, Dietrich PY, Ostermann Kraljevic S, Pica A, Maillard I, Maeder P, Meuli R, Janzer 
R, Pizzolato G, Miralbell R, Porchet F, Regli L, de Tribolet N, Mirimanoff RO, Leyvraz S. 
Promising survival for patients with newly diagnosed glioblastoma multiforme treated with 
concomitant radiation plus temozolomide followed by adjuvant temozolomide.  J Clin Oncol. 
2002 Mar 1;20(5):1375-82. 
 
4.  Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP. Meta-analysis of radiation therapy 
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15;71(8):2585-97. 
 
5.  Mirimanoff R, Mason W, Kortmann R, Van Den Bent M, Fisher B, Taphoorn M, Reni M, 
Curschmann J, Villa S, Cairncross G, Gorlia T, Stupp R. Radiotherapy (RT) and Concomitant 
and Adjuvant Temozolomide (TMZ) versus Radiotherapy Alone for Newly Diagnosed 
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Randomized Trial of the EORTC Brain Tumor and Radiotherapy Groups and the NCIC Clinical 
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6.  Hegi M, Diserens A, Hamou M, Gorlia T, Weller M, Kros J,  Hainfellner J, Bogdahn U, 
Cairncross Jg, Stupp R. Temozolomide (TMZ)targets only glioblastoma with a silenced MGMT- 
gene. Results of a translational companion study to EORTC 26981/NCIC CE.3 or radiotherapy ± 
TMZ. Eur J Cancer (Suppl 2): 14 {abs. 31}, 2004 
 
7.  Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, 
Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier 
A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for 
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8.  Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner 
JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, 
Stupp R.  MGMT gene silencing and benefit from temozolomide in glioblastoma.  N 
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9.  Stevens MF, Hickman JA, Langdon SP, Chubb D, Vickers L, Stone R, Baig G, Goddard C, 
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11. Wick W, Steinbach JP, Kuker WM, Dichgans J, Bamberg M, Weller M. One week on/one 
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12.  Bocci G, Nicolaou KC, Kerbel RS.  Protracted low-dose effects on human endothelial cell 
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13.   Wang J, Lou P, Lesniewski R, Henkin J.  Paclitaxel at ultra low concentrations inhibits 
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Anticancer Drugs. 2003 Jan;14(1):13-9. 
 
14.  Bocci G, Francia G, Man S, Lawler J, Kerbel RS.  Thrombospondin 1, a mediator of the 
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Schwartz G, Edwards T, Reyderman L, Statkevich P, Cutler DL, Rowinsky EK.  Marked 
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20.0 
APPENDICES