Clinical trial NCT01822275
Conditions: Histologically Proven Diagnosis of Glioblastoma or Gliosarcoma (WHO Grade IV)
Keywords: GBM
Sponsor: University of Maryland, Baltimore
Start date: 2013-05-01; Completion date: 2019-09-01
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In the current proposed trial the role of the low-dose WBRT (0.15 Gy) would be to safely treat the microscopic distant GBM cells outside of the high dose RT region and sensitize the gross tumor, while the focal radiation dose (1.85 Gy) to the gross tumor will bring the total tumor dose of 2 Gy per fraction which is the standard of care.

Radiotherapy (RT) has been integral in the treatment of GBM since the 1970s when Walker et al. showed that post-operative whole brain radiotherapy (WBRT) offered significant improvements in median survival time, and even more so when given with concomitant BCNU chemotherapy. Ensuing dose escalation studies found the optimal dose to be 60 Gy. Patients could not tolerate escalation to higher doses than 60 Gy with WBRT due to unacceptable toxicity. Even with WBRT of 60 Gy, a huge volume of healthy brain tissue was unnecessarily treated with high-dose radiation; recurrences with WBRT remained overwhelmingly local. Hochberg and Pruitt (1980) found that after WBRT only 3% of recurrences were outside 2 cm of the margins of the primary tumor. With the rise of the CT scan in the 1980s and the MRI in the 1990s, along with subsequent improvements in three-dimensional conformal radiation, partial brain RT (PBRT) became practical since tumor margins could be visualized and irradiated more accurately. - Subsequently, WBRT was shown to provide no survival benefit over PBRT at the same dosage; - thus, the latter took over as the standard of care.

Detailed description:
Radiation Therapy (RT) has been integral in the treatment of GBM since the 1970s. Studies showed that post-operative whole brain radiotherapy (WBRT) offered significant improvements in median survival time, and even more so when given with chemotherapy. Even with WBRT, a huge volume of healthy brain tissue was unnecessarily treated with high-dose radiation; re-growth of tumor with WBRT remained overwhelmingly close to the original tumor site. With the advances in imaging techniques, like CT scans and MRIs, partial brain RT (PBRT) has become a common practice. PBRT is RT given only to the tumor or area of the brain where the cancer was removed. PBRT given with a drug called temozolomide (TMZ) is used as the standard of care treatment for newly diagnosed GBM after surgery.

Current data from our institution suggests that the combination of TMZ with very low-dose WBRT efficiently kills GBM cells. WBRT at conventional higher doses is not given at the same time as TMZ since the severe toxicity risk would be too risky. However, a lower daily WBRT dose, than what is conventionally given to patients, should be tolerable. The randomized trials studying TMZ with low-dose WBRT in patients with brain metastasis did not demonstrate increased serious toxicities associated with TMZ.

PURPOSE OF STUDY Why is the research study being done? The purpose of this study is to determine if low-dose WBRT given in combination with the standard of care TMZ regimen is safe and effective. The role of the low-dose WBRT would be to safely treat the microscopic distant GBM cells outside of the high-dose PBRT region. We will continue to target the tumor with focused PBRT that will bring the total tumor dose to the standard of care dose. This study will find out what effects, good or bad, low-dose WBRT has on you and your cancer.

PROCEDURES How many people will take part in the study? About 47 people will take part in this study. Patient participation in this study is voluntary. The research will be conducted at UMMS.

What will happen if I take part in this research study? Before you begin the study… Patient will need to have the following exams, tests or procedures to find out if you can be in the study. These exams, tests or procedures are part of regular cancer care and may be done even if Patient does not join the study. If he/she has had some of them recently, they may not need to be repeated. This will be up to the study doctor.

* History and physical with neurological examination
* Brain MRI with contrast
* Blood tests (about 2-3 teaspoons of blood will be taken from the vein)
* Pregnancy test for women of childbearing potential

During the study… The experimental part of this study is that the patient will receive low-dose WBRT. If the tests show that the patient can be in the study, and he/she chooses to take part, patient will receive low-dose WBRT at the same time as standard PBRT. The patient will receive RT once daily, 5 days a week (Monday through Friday) for 6 weeks (a total of 30 treatments). Each treatment lasts for no more than 30 minutes. Treatment will begin 3-6 weeks after your last surgery.

At the same time as RT you will take oral TMZ once a day. TMZ will be taken continuously from the night before the first day of RT to the last day of RT (maximum of 49 days). The pills should be swallowed whole and taken on an empty stomach, therefore a minimum of 2 hours after eating and with no food consumption for at least 1 hour after TMZ administration. The drug will be taken at night.

About 4 weeks after you finish RT and TMZ, you will begin 28 day cycles of TMZ alone. You will take TMZ orally on the first 5 days of each cycle. Again, the pills should swallowed whole and taken on an empty stomach, therefore a minimum of 2 hours after eating and with no food consumption for at least 1 hour after TMZ administration. You should take the TMZ at night.

If patient misses any dose of TMZ, it will not be made up the next day.

The patient will be treated with post-radiation TMZ for 6 cycles unless there is evidence of tumor progression or treatment-related toxicity. Patients demonstrating continued benefit from the adjuvant treatment can continue treatment to a maximum of 12 cycles at the discretion of the treating physician.

If the exams, tests and procedures show that the patient can be in the study, and they choose to take part, then he/she will need the following tests and procedures. They are part of regular cancer care.

Weekly during RT and TMZ:

* Patient evaluation with toxicity assessment
* Blood tests (about 2-3 teaspoons of blood will be taken from the vein)

Prior to starting each cycle of TMZ alone:

* History and physical with neurological examination and toxicity assessment
* Blood tests (about 2-3 teaspoons of blood will be taken from the vein)
* Prior to cycle 1 and then every 2-3 months, a brain MRI with contrast

Blood tests (about 2-3 teaspoons of blood will be taken from your vein) will also be performed at about 2 and 3 weeks (days 14 and 21 (± 2days)) after starting cycle 1 and cycle 2 of TMZ alone

During follow-up…

Once patient has completed all the cycles of TMZ the patient will be seen every 1-3 months for the first two years (years 1-2), 3-6 months for the next 2 years (years 3-4), and then annually starting at year 5. During these follow-up visits the patient will have the following tests and procedures performed:

* History and physical with neurological examination and toxicity assessment
* Brain MRI with contrast
* Any other test deemed medically necessary

The doctors would like to keep track of the medical condition for the rest of the patient's life. Keeping in touch with the patient and checking on their condition yearly helps the physicians to look at the long-term effects of the study.

Arms: arm 1: Once the patient has had surgery, patients will receive 6 weeks of radiation therapy with concurrent chemotherapy on protcol. This will be followed by either 6 or a maximum of 12 cycles of adjuvent chemotherapy with Temodar.
Interventions: intervention 1: Chemotherapy with Temodar. intervention 2: Radiation therapy
Intervention descriptions: intervention 1: Once the patient has had surgery, patients will receive 6 weeks of radiation therapy with concurrent chemotherapy on protcol. This will be followed by a maximum of 12 cycles of adjuvent chemotherapy with Temodar. intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
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GCC 1224 
(HP-00053043) 
 
Phase II Trial of Low-Dose Whole Brain Radiotherapy with Concurrent 
Temozolomide and Adjuvant Temozolomide in Patients with Newly-Diagnosed 
Glioblastoma Multiforme 
 
Version: 01June2018 
 
 
Principal Investigator 
Young Kwok, M.D. 
Associate Professor 
Univ of Maryland School of Medicine 
Department of Radiation Oncology 
22 S Greene St 
Baltimore, MD 21201 
Tel:  410-328-9134 
Fax: 410-328-5279 
Email: ykwok@umm.edu 
 
Co-Principle Investigators 
France Carrier, Ph.D. 
Associate Professor 
Univ of Maryland School of Medicine 
Department of Radiation Oncology 
655 West Baltimore Street, Rm 10-037 
Baltimore, MD 21201 
Tel:  410-706-5105 
Fax: 410-706-3260 
Email: fcarr001@umaryland.edu 
 
Edward Sausville, M.D. 
Professor 
Univ of Maryland School of Medicine 
Greenebaum Cancer Center 
22 S Greene St 
Baltimore, MD 21201 
 
William Regine, M.D. 
Professor 
Univ of Maryland School of Medicine 
Department of Radiation Oncology 
22 S Greene St 
Baltimore, MD 21201 
 
Research Associate, Point of Contact 
Caroline Poff, MS, RN 
Department of Radiation Oncology 
Email: caroline.poff@umm.edu 
Tel: 
410-369-5264 
Fax: 410-347-0870 
 
Statistician 
Christopher Morris, B.S. 
University of Florida, Gainesville 
Email: morricg@gmail.com 
 


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INDEX 
 
 
Schema 
3 
1.0 
Introduction 
4 
2.0 
Objectives 
6 
3.0 
Patient Selection 
6 
4.0 
Treatment Evaluations/Management 
9 
5.0 
Study Design and Treatment Plan 
10 
6.0 
Radiation Therapy 
12 
7.0 
Drug Therapy 
15 
8.0 
Surgery and Other Therapy 
24 
9.0 
Statistical Considerations 
25 
10.0 
References 
27 
 
 


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TREATMENT SCHEMA 
 
Weeks 1-6 
 
Concurrent RT+TMZ 
 
TMZ 75 mg/m2 / day 
 
RT = 2.0 Gy/day (5 days/week) x 30 
fractions, total 60 Gy as follows: 
 
RT 0.15 Gy/day Whole Brain 
+ 
RT 1.85 Gy/day Partial Brain 
 
 
Optional PCP prophylaxis 
Adjuvant TMZ 
(4 weeks (+/- 3 days)) after the completion of RT) 
 
Standard Adjuvant TMZ (28 day cycle) 
 
TMZ 150 mg/m2 / day, Days 1-5, Cycle # 1 
 
TMZ 200 mg/m2 / day, Days 1-5, Starting Cycle # 2 
 
TMZ total of 6-12 cycles or until disease 
progression 
 
Optional Tumor Treating Fields 
 
Optional PCP prophylaxis 
 
 TMZ = Temozolomide; RT = Radiation Therapy; Partial Brain = Planning Target 
Volume (PTV); PCP = pneumocystis carinii (jirovecii) pneumonia. 
 
 Both the whole and partial brain RT will be given per day, giving the standard of 
care total of 2 Gy per day to the tumor, 5 days per week for a total of 60 Gy over 
6 weeks. 
 
 All Patients will receive the standard TMZ (Stupp regimen) during and after the 
completion of RT. 
 
 RT/TMZ are to commence 3-6 weeks after surgery (can be biopsy only).  If 
multiple surgeries are required (resection, abscess drainage, etc), then RT 
should commence not before 3 weeks, but no later than 6 weeks after the last 
surgical procedure. 


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1.0  INTRODUCTION 
 
1.1 
Background 
Glioblastoma multiforme (GBM) is the most common of all adult malignant 
primary brain tumors and portends a very poor prognosis.  Glioblastomas (World 
Health Organization [WHO] grade IV astrocytomas) comprise approximately 15% 
of all primary brain tumors, and the incidence is 2-3 new cases per 100,000 
people per year.1-2  In adults, GBM is almost always located in the cerebral 
hemispheres; though, rarely tumors may affect the brainstem or spinal cord.1  
Lower-grade astrocytomas (WHO grades II or III) can progress to GBM, but in 
the majority of cases (60%) glioblastomas develop de novo.1  In cases of primary 
GBM, symptoms typically appear less than 3 months prior to diagnosis.1  
Common symptoms include headaches, nausea/vomiting, fatigue, personality 
changes, memory loss, and the development of neurological deficits.  The pivotal 
Stupp trial, which set the current standard of care, demonstrated median, 2-year, 
and 5-year survivals of 14.6 months, 27%, and 10% respectively.3-4  There are 
almost no long-term survivors. 
 
Radiotherapy (RT) has been integral in the treatment of GBM since the 1970s 
when Walker et al. showed that post-operative whole brain radiotherapy (WBRT) 
offered significant improvements in median survival time, and even more so 
when given with concomitant BCNU chemotherapy.5  Ensuing dose escalation 
studies found the optimal dose to be 60 Gy.6  Patients could not tolerate 
escalation to higher doses than 60 Gy with WBRT due to unacceptable toxicity.  
Even with WBRT of 60 Gy, a huge volume of healthy brain tissue was 
unnecessarily treated with high-dose radiation; recurrences with WBRT remained 
overwhelmingly local.7  Hochberg and Pruitt (1980) found that after WBRT only 
3% of recurrences were outside 2 cm of the margins of the primary tumor.8  With 
the rise of the CT scan in the 1980s and the MRI in the 1990s, along with 
subsequent improvements in three-dimensional conformal radiation, partial brain 
RT (PBRT) became practical since tumor margins could be visualized and 
irradiated more accurately.9-10  Subsequently, WBRT was shown to provide no 
survival benefit over PBRT at the same dosage;11-12 thus, the latter took over as 
the standard of care. 
 
1.2 
Role of Temozolomide 
Until 2005, the standard of care was surgical resection, with post-operative RT 
alone or in combination with BCNU chemotherapy.  Recurrences with PBRT still 
occurred almost exclusively within the field of the RT.13-14  In fact, Chan et al. 
(2002) found that despite RT dose escalation to 90 Gy, failure patterns remained 
local.10  Patients were not living long enough for distant failures to develop; 
median survival was still approximately less than one year after diagnosis.15,16,17 
 
After the chemotherapy drug temozolomide (TMZ), an oral alkylating agent of the 
imidazotetrazine derivatives, demonstrated antitumor activity as a single agent, 
and then concomitantly with RT in a phase II trial,18 the European Organisation 


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for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups 
(EORTC) and the National Cancer Institute of Canada (NCIC) commissioned a 
phase III trial to compare this regimen with RT alone in patients with newly 
diagnosed GBM.  TMZ has modest single agent efficacy and acts as a 
radiosensitizer.  In this phase III trial reported by Stupp et al, the median survival 
was 12.1 months with RT alone, and 14.6 months with RT plus TMZ, with 
minimal additional toxicity.4  Furthermore, the two year-survival rate was 10.4% 
with RT alone, and 26.5% with RT plus TMZ (p < 0.001).  In the follow-up study it 
was shown that the benefits and survival advantage of adding adjuvant TMZ to 
treatment lasted throughout 5 years of follow-up (p < 0.0001).3  Thus, RT (60 Gy 
given in 2 Gy fractions) plus concomitant and adjuvant TMZ has become the 
standard of care. 
 
1.3 
Treatment Failure Patterns in the Temozolomide Era 
With the advent of TMZ and RT, the overall survival has increased due to 
improved local control; consequently, distant failure outside of the RT field has 
greatly increased in frequency.  Brandes et al (2009) found that with treatment of 
RT plus TMZ, 28% of recurrences were outside the high dose PBRT field.19  
Also, recurrences outside the RT field occurred after a longer period of time than 
recurrences inside the RT field.  It is theorized that once local tumor control has 
been achieved, the malignant cells outside the RT field remain and are able to 
proliferate.  Indeed, classic autopsy series have demonstrated malignant cells 
very distant from the edge of the dominant tumor.20  So it is clear that now that as 
GBM patients are experiencing longer survivals, distant brain failures are 
becoming a more frequent. 
 
1.4 
Low-dose Radiation 
 
 
Recent presented data from our institution (above figure, ASTRO 2011) suggest 
that the combination of TMZ with very low-dose RT (0.15 Gy) proves significantly 


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toxic to GBM cell lines (70% reduction in survival rates).21  It is thought that such 
low-dose RT is able to damage cellular DNA and induce apoptosis without 
activating DNA repair mechanisms. TMZ acts as radiosensitizer when given 
concurrently with radiation therapy. 
 
Again, WBRT at conventional doses (60 Gy in 2 Gy fractions) is not given with 
concurrent TMZ since the severe toxicity risk would be prohibitive.  However, 
fractions of 0.15-0.5 Gy, an order of magnitude less than what is conventionally 
given to patients, should be very tolerable if WBRT is given.  The randomized 
trials studying concurrent TMZ and whole brain RT (WBRT) in patients with brain 
metastasis did not demonstrate increased serious toxicities associated with 
TMZ.22,23  These trials had 2 Gy fractions to 40 Gy [Antonadou, 2002] and 3 Gy 
fractions to 30 Gy [Verger, 2005].  All available information suggests no 
overlapping or problematic toxicities will result from the low-dose WBRT given 
with TMZ.  It is highly doubtful that low-dose WBRT of 0.15 Gy per day will be 
toxic since it is a whole magnitude less than utilized in these randomized trials, 
but since no phase I data exist for this specific treatment combination, this study 
is intended to determine the safety and efficacy of low-dose WBRT given in 
combination with the standard of care TMZ. 
 
In the current proposed trial the role of the low-dose WBRT (0.15 Gy) would be to 
safely treat the microscopic distant GBM cells outside of the high dose RT region 
and sensitize the gross tumor, while the focal radiation dose (1.85 Gy) to the 
gross tumor will bring the total tumor dose of 2 Gy per fraction which is the 
standard of care. 
 
2.0  OBJECTIVES 
 
2.1 
Primary Objective 
To determine the safety and efficacy of low-dose whole brain RT (WBRT) when 
given concurrently to the standard TMZ and focal partial brain RT (efficacy will be 
measured by decreased distant disease recurrence rate). 
 
2.2 
Secondary Objectives 
2.2.1 To determine the radiographic response with the combination therapy. 
2.2.2 To determine the treatment failure patterns after the combination therapy. 
 
3.0  PATIENT SELECTION 
 
3.1 
Conditions for Patient Eligibility 
3.1.1 Histologically proven diagnosis of glioblastoma or gliosarcoma (WHO 
grade IV). 
3.1.2 Infratentorial are eligible. 
3.1.3 History 
and 
physical 
with 
neurological 
examination, 
steroid 
documentation, height, and weight within 14 days of registration. 


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3.1.4 A diagnostic contrast-enhanced MRI of the brain must be performed 
preoperatively and postoperatively prior to the initiation of radiotherapy.  The 
postoperative scan must be performed within 28 days prior to registration.  
(Please note: Contrast enhanced Brain CT is allowed if MRI is contraindicated.) 
3.1.5 Karnofsky performance status ≥ 70 or ECOG performance status ≤ 2. 
3.1.6 Age ≥ 18. 
3.1.7 CBC with differential obtained within 14 days prior to registration, with 
adequate bone marrow function defined as follows: 
 Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3. 
 Platelets ≥ 100,000 cells/mm3. 
 Hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other 
intervention to achieve Hgb ≥10.0 g/dl is acceptable). 
3.1.8 Adequate renal function within 14 days prior to registration, as defined 
below: 
 BUN ≤ 30 mg/dl. 
 Creatinine ≤ 1.7 mg/dl. 
3.1.9 Adequate hepatic function within 14 days prior to registration, as defined 
below: 
 Bilirubin ≤ 2.0 mg/dl. 
 ALT/AST ≤ 3 x upper limit of normal (ULN). 
Please note that if the liver function tests are abnormal, the decision to initiate 
temozolomide treatment should carefully consider the benefits and risks to the 
individual patient. 
3.1.10 Systolic blood pressure ≤ 160 mg Hg or diastolic pressure ≤ 90 mg Hg 
within 14 days prior to registration. 
3.1.11 Patient must provide study specific informed consent prior to study entry. 
3.1.12 For women of child-bearing potential, negative serum pregnancy test 
within 14 days prior to registration. 
3.1.13 Women of childbearing potential and male participants must practice 
adequate contraception. 
 
3.2 
Conditions for Patient Ineligibility 
3.2.1 Prior invasive malignancy (except for non-melanomatous skin cancer) 
unless disease free for ≥ 3 years.  For example, carcinoma in situ of the breast, 
oral cavity, and cervix are all permissible. 
3.2.2 Metastases beyond the cranial vault. 
3.2.3 Prior use of Gliadel wafers or any other intratumoral or intracavitary 
treatment is not permitted. 
3.2.4 Prior radiotherapy to the head or neck (except for T1 glottic cancer), 
resulting in significant overlap of radiation fields. 
3.2.5 Severe, active co-morbidity, defined as follows: 
 Unstable angina and/or congestive heart failure within the last 6 
months. 
 Transmural myocardial infarction within the last 6 months. 
 New York Heart Association grade II or greater congestive heart 
failure requiring hospitalization within 12 months prior to registration. 


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 History of stroke, cerebral vascular accident (CVA) or transient 
ischemic attack within 6 months. 
 Serious and inadequately controlled cardiac arrhythmia. 
 Significant vascular disease (e.g., aortic aneurysm, history of aortic 
dissection) or clinically significant peripheral vascular disease. 
 Evidence of bleeding diathesis or coagulopathy. 
 Serious or non-healing wound, ulcer, or bone fracture or history of 
abdominal fistula, gastrointestinal perforation or intra-abdominal 
abscess, major surgical procedure or significant traumatic injury within 
28 days prior to registration, with the exception of the craniotomy for 
tumor resection or follow-on craniotomies to manage complications of 
brain tumor management such as hemorrhage or infection. 
 Bacterial or fungal infection requiring intravenous antibiotics at the 
time of registration. 
 Chronic obstructive pulmonary disease exacerbation or other 
respiratory illness requiring hospitalization or precluding study therapy 
at the time of registration. 
 Hepatic insufficiency resulting in clinical jaundice and/or coagulation 
defects; note, however, that laboratory tests for coagulation 
parameters are not required for entry into this protocol. 
 Acquired immune deficiency syndrome (AIDS) based upon current 
CDC definition; Note, however, that HIV testing is not required for 
entry into this protocol.  The need to exclude patients with AIDS from 
this protocol is necessary because the treatments involved in this 
protocol are significantly immunosuppressive. 
 Active connective tissue disorders such as lupus or scleroderma that, 
in the opinion of the treating physician, may put the patient at high risk 
for radiation toxicity. 
 Any other major medical illnesses or psychiatric impairments that in 
the investigator's opinion will prevent administration or completion of 
protocol therapy. 
 Cognitive impairment that precludes a patient from acting as his or her 
own agent to provide informed consent. 
3.2.6 Women of childbearing potential and men who are sexually active and not 
willing/able to use medically acceptable forms of contraception; this exclusion is 
necessary because the chemotherapeutic treatment involved in this study is 
significantly teratogenic. 
3.2.7 Pregnant or lactating women, due to possible adverse effects on the 
developing fetus or infant due to study treatment. 
3.2.8 Patients treated on any other therapeutic clinical protocols within 30 days 
prior to study entry or during participation in the study. 
3.2.9 Multi-focal tumors are ineligible 
 
4.0  PATIENT TREATMENT EVALUATIONS 
 
4.1 
Within 14 days of registration: 


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4.1.1 History and Physical with neurological exam and steroid documentation. 
4.1.2 Complete Blood Count (CBC) with differential. 
4.1.3 Comprehensive metabolic panel (CMP) including Liver Function Tests. 
 
4.2 
Within 28 days of registration: 
4.2.1 Post-operative, contrast-enhanced MRI of the brain (contrast enhanced 
Brain CT is allowed if MRI is contraindicated). 
 
4.3 
During TMZ and RT: 
4.3.1 CBC with differential and CMP including Liver Function Tests will be done 
every 2 weeks. 
4.3.2 Weekly patient evaluation with toxicity assessment. 
 
4.4 
During Adjuvant TMZ: 
4.4.1 History and physical with neurological exam, steroid documentation, and 
toxicity assessment within 7 days prior to starting each cycle. 
4.4.2 CBC with differential and CMP including Liver Function Tests will be done 
within 7 days prior to starting new cycle. 
4.4.3 Brain MRI with contrast (contrast enhanced Brain CT is allowed if MRI is 
contraindicated) prior to cycle 1 and then every 2-3 months till the end of 
Adjuvant TMZ. 
 
4.5 
Standard of Care Follow-Up Assessments (to begin after completion of Adjuvant 
TMZ): 
4.5.1 Follow-up schedule: 
 Every 1-3 months for the first 2 years (years 1-2). 
 Every 3-6 months for the next 2 years (years 3-4). 
 Annually starting at year 5. 
4.5.2 At each follow-up visit: 
 History and physical with neurological exam and toxicity assessment. 
 MRI of the brain with contrast (contrast enhanced Brain CT if MRI is 
contraindicated): 
o Usually, every 2-3 months for first 2 years.  However, the frequency 
is at the discretion of the physician and, thus, it may be performed 
more frequently if medically necessary. 
o MRI perfusion and spectroscopic examinations are allowed at any 
time, if clinically indicated. 
 Any other test deemed medically necessary. 
 
4.6 
If the patient progresses at any time during treatment, the patient will be 
considered off protocol.  Any treatment and follow-up after that time will be at the 
discretion of the treating physician. 
 
5.0  STUDY DESIGN AND TREATMENT SUMMARY 
 
TREATMENT SCHEMA 


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Weeks 1-6 
 
Concurrent RT+TMZ 
 
TMZ 75 mg/m2 / day 
 
RT = 2.0 Gy/day (5 days/week) x 30 
fractions, total 60 Gy as follows: 
 
RT 0.15 Gy/day Whole Brain 
+ 
RT 1.85 Gy/day Partial Brain 
 
Optional PCP prophylaxis 
Adjuvant TMZ 
(4 weeks (+/- 3 days)) after the completion of RT) 
 
Standard Adjuvant TMZ (28 day cycle) 
 
TMZ 150 mg/m2 / day, Days 1-5, Cycle # 1 
 
TMZ 200 mg/m2 / day, Days 1-5, Starting Cycle # 2 
 
TMZ total of 6-12 cycles or until disease 
progression 
 
Optional PCP prophylaxis 
 
 TMZ = Temozolomide; RT = Radiation Therapy; Partial Brain = Planning Target 
Volume (PTV); PCP = pneumocystis carinii (jirovecii) pneumonia. 
 Both the whole and partial brain RT will be given per day, giving the standard of 
care total of 2 Gy per day to the tumor, 5 days per week for a total of 60 Gy over 
6 weeks. 
 All Patients will receive the standard TMZ (Stupp regimen) during and after the 
completion of RT. 
 RT/TMZ are to commence 3-6 weeks after surgery (can be biopsy only).  If 
multiple surgeries are required (resection, abscess drainage, etc), then RT 
should commence not before 3 weeks, but no later than 6 weeks after the last 
surgical procedure. 
 
Patients can only be enrolled after all eligibility criteria are met.  The date of 
registration/enrollment is considered to be the day the Eligibility Checklist is signed by 
the verifying physician.  Once a patient is enrolled, a unique case number will be 
assigned to the patient. 
 
 
 
5.1 
Safety and efficacy 
It is highly doubtful that low-dose WBRT of 0.15 Gy per day will have any 
significant side-effects.  However, since no study has been performed to test this 
regimen, this study will test the safety and efficacy of low-dose WBRT with 
concurrent TMZ.  A total of 47 patients will be enrolled on this study, with a 
mandatory interim review after the first 6 patients.  A dose-limiting toxicity (DLT) 
will be assessed from the first day of treatment with TMZ (the night prior to 
starting RT or TMZ can be started within 24 hours of first RT treatment) to 1 
month after the completion of RT.  Thus, the 7th patient cannot be enrolled until 
all 6 patients have been assessed for 1 month after the completion of RT.  Low-
dose WBRT will be deemed safe and effective if no more than 1 out of 6 patients’ 


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experiences a DLT as defined below.  If 2 or more patients experience a DLT, 
then low-dose WBRT at this dose of 0.15 Gy will be deemed unsafe, and the trial 
will close. 
 
5.2 
Definition of Dose-Limiting Toxicity (DLT) 
Toxicities will be graded according to the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0.  If multiple toxicities are seen, 
the presence of DLT should be based on the most severe toxicity experienced.  
DLT will be defined as any of the following events occurring during treatment with 
TMZ and RT, and attributable (probably related) to the study regimen: 
 Any grade 4 thrombocytopenia, grade 4 anemia, or grade 4 
neutropenia with fever (> 100.4F) or grade 4 neutropenia lasting 
more than 7 days. 
 Any non-hematologic grade 3 or greater toxicity (excluding alopecia) 
maintained despite maximal medical therapy 72 hours after maximal 
medical therapy is instituted; except infection, seizure, deep venous 
thrombosis (DVT) or pulmonary embolism (PE).  The reason for this 
exclusion is that seizures, DVT and/or PE are very common in the 
glioblastoma multiforme population, are conventionally treated without 
interruption of the primary brain tumor treatment, and their existence 
does not influence the decision to go forward with completion of 
chemoradiation to otherwise qualifying patients.  Management of DVT 
with or without PE conventionally involves insertion of a Greenfield 
filter and consideration of anticoagulation to a dose and degree that is 
dependent on a consideration of individual comorbidities and 
individualized for each patient.  Thus the occurrence of DVT or PE will 
not influence a consideration of the feasibility of adding low-dose 
WBRT.  Management of seizures conventionally can involve 
consultation with neurology and the regimen employed likewise does 
not influence completion of chemoradiation.  Management of infection 
occurs via the standard of care unless due to accompanying grade 4 
neutropenia as described above. 
 
Please Note: non-hematologic toxicities such as rash, nausea, vomiting, 
diarrhea, mucositis, hypophosphatemia, and hypertension will only be considered 
DLTs if they remain grade 3 or greater despite maximal medical therapy 72 hours 
after maximal medical therapy is instituted. 
 
5.3 
Temozolomide 
This will follow the standard Stupp regimen with optional PCP prophylaxis.  The 
decision to start and the choice PCP prophylaxis is up to the discretion of the 
treating physician 
5.3.1 During RT: TMZ 75 mg/m2 / day from the evening before the first dose of 
RT to the last day of RT.  Please note that TMZ can be started within 24 hours of 
first fraction of Radiation Treatment (± 1 day of RT). 
5.3.2 Adjuvant treatment: 


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 Cycle #1: TMZ 150 mg/m2 / day on days 1-5 of a 28 day cycle. 
 Cycle #2 (and all subsequent cycles): TMZ 200 mg/m2 / day on days 
1-5 of a 28 day cycle. 
 TMZ regimen can be switched to TMZ 75 mg/m2 / day on days 1-21 of 
a 28 day cycle at the treating physician’s discretion. 
 
5.4 
Radiation Therapy 
The radiation dose will remain the same for all patients and is to begin 3-6 weeks 
after the last craniotomy (i.e., if multiple procedures).  All patients will receive 
0.15 Gy of WBRT, followed by a partial brain boost dose of 1.85 Gy, bringing the 
standard of care total dose of 2.0 Gy to the tumor each day, 5 days per week to a 
total dose of 60 Gy. 
 
5.5 
Distant Failure Definition 
Definition 
per 
Brandes 
et 
al19: 
80% 
or 
more 
of 
the 
volume 
of 
recurrent/progressive tumor must be outside of the 95% isodose line; or any 
volume non-contiguous tumor (separate nodule) occurring outside of the 95% 
isodose line. 
 
6.0  RADIATION THERAPY 
 
6.1 
Timing of Radiation Therapy 
RT will begin no earlier than 3 weeks and no later than 6 weeks after surgery.  If 
multiple procedures (e.g., resection, abscess draining, etc) are required, then the 
timing of RT will begin after the final procedure. 
 
6.2 
Technical Factors 
Treatment shall be delivered with megavoltage machines of a minimum energy of 
6 MV photons.  Selection of the appropriate photon energy(ies) should be based 
on optimizing the radiation dose distribution within the target volume and 
minimizing dose to non-target normal tissue.  Source skin distance for SSD 
techniques or source axis distance for SAD techniques must be at least 80 cm.  
Electron, particle, planned radiosurgery or implant boost is not permissible. 
 
6.3 
Localization, Simulation, and Immobilization 
The patient shall be treated in the supine or other appropriate position for the 
location of the lesion.  A head-holding device and a mouth piece to ensure 
adequate immobilization during therapy and ensure reproducibility are strongly 
recommended.  A treatment planning CT is mandatory.  The entire cranial 
contents down to the lower cervical spine should be scanned in 1-3 mm slice 
thickness.  Intravenous contrast while permitted is usually not necessary since 
post-operative MRI fusion will be utilized for planning.  Daily image guidance 
(e.g., MV, KV, CT imaging) for localization is strongly recommended. 
 
6.4 
Treatment Planning/Target Volumes 


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Treatment plans may include opposed lateral fields, a wedge pair of fields, 
rotation, or multiple field techniques.  Intensity-modulated Radiation Therapy 
(IMRT) is permitted.  Any of the methods of IMRT may be used.  CT-based 
treatment planning is necessary to assure accuracy in the selection of field 
arrangements.  MRI-fusion for accurate target delineation is strongly 
recommended.  RT will begin no earlier than 3 weeks and no later than 6 weeks 
after craniotomy (after the last surgery if multiple procedures). 
6.4.1 Initial Target Volume (PTV1): Target volumes will be based upon 
postoperative-enhanced MRI.  Preoperative imaging should be used for 
correlation and improved identification.  The initial gross tumor volume (GTV1T) 
will be defined by either the T2 or the FLAIR abnormality on the postoperative 
MRI scan.  This must also include all postoperative-enhanced MRI enhancement 
and the surgical cavity.  The initial clinical target volume (CTV1T) will be the 
GTV1T plus a margin of 1.5 cm.  If no surrounding edema is present or if the 
edema is judged by the treating physician to be too large for safety delivery of 
radiation, the initial clinical target volume (CTV1T) should include the contrast-
enhancing lesion (and should include the surgical resection cavity) plus a 1.5 cm 
margin.  The CTV1T margin may be reduced to as low 0 cm around natural 
barriers to tumor growth such as the skull, ventricles, falx, etc, and also to allow 
sparing of the normal tissues, if necessary.  The initial planning target volume 
(PTV1T) is an additional margin of 3 to 5 mm, depending upon localization 
method and reproducibility.  PTV margins account for variations in set-up and 
reproducibility.  However, this may reduced to as low as 0 cm around natural 
barriers to tumor growth or to allow sparing of normal tissues.   
The dose to PTV1T will be 1.85 Gy per day for 5 days per week.  All patients will 
receive low-dose WBRT (PTV1W).  The standard WBRT will be utilized (inferior 
border being at C1/2 cervical space) using the opposed lateral technique.  The 
dose to PTV1W will be 0.15 Gy per day for 5 days per week.  Thus, a total dose 
(PTV1) will be the standard of care 2.0 Gy per day (1.85 Gy + 0.15 Gy) for 23 
daily fractions for a total of 46 Gy. 
 
Low-dose WBRT: 
 
 
PTV1W  =  0.15 Gy/day 
Partial brain RT: 
 
 
PTV1T   =  1.85 Gy/day 
Total:  
 
 
 
PTV1    =  2.00 Gy/day  x 23 = 46 Gy 
 
6.4.2 Boost Target Volume (PTV2): The gross tumor volume (GTV2T) will be 
defined by the T1 abnormality on the postoperative MRI scan.  This must include 
all postoperative-enhanced MRI enhancement and the surgical cavity.  The initial 
clinical target volume (CTV2T) will be the GTV2T plus a margin of 1.5 cm.  The 
CTV2T margin may be reduced to as low 0 cm around natural barriers to tumor 
growth such as the skull, ventricles, falx, etc, and also to allow sparing of the 
normal tissues, if necessary.  The initial planning target volume (PTV2T) is an 
additional margin of 3 to 5 mm, depending upon localization method and 
reproducibility.  PTV margins account for variations in set-up and reproducibility.  
However, this may reduced to as low as 0 cm around natural barriers to tumor 
growth or to allow sparing of normal tissues.   


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The dose to PTV2T will be 1.85 Gy per day for 5 days per week.  All patients will 
receive low-dose WBRT (PTV2W).  The standard WBRT will be utilized (inferior 
border being at C1/2 cervical space) using the opposed lateral technique.  The 
dose to PTV2W will be 0.15 Gy per day for 5 days per week.  Thus, a total dose 
(PTV2) will be the standard of care 2.0 Gy per day (1.85 Gy + 0.15 Gy) for 7 daily 
fractions for a total of 14 Gy. 
 
Low-dose WBRT: 
 
 
PTV2W  =  0.15 Gy/day 
Partial brain RT: 
 
 
PTV2T   =  1.85 Gy/day 
Total:  
 
 
 
PTV2    =  2.00 Gy/day  x 7 = 14 Gy 
 
In summary: 
PTV1: 2 Gy x 23 = 46 Gy 
PTV2: 2 Gy x   7 = 14 Gy 
Total:  
     = 60 Gy 
 
6.5 
Dose Limitation to Critical Structures 
In addition to the above defined GTVs, CTVs and PTVs, the lenses of both eyes, 
both retinae (as outlined as the whole globe), both lacrimal glands, both optic 
nerves, the optic chiasm, and the brainstem must be defined.  The maximum 
point (defined as a volume greater than 0.03 cc) doses (and mean dose for 
lacrimal glands) permissible to the structures are listed in the table below. 
 
Critical Structure 
Maximum Dose (> 0.03 cc) 
Lenses 
7 Gy 
Retinae 
50 Gy 
Optic Nerves 
55 Gy 
Optic Chiasm 
56 Gy 
Brainstem 
60 Gy 
Lacrimal Glands 
26 Gy (mean dose) 
 
 
6.6 
Treatment Planning Goals 
6.6.1 100% of the PTV volume should be covered by the 95% isodose line. 
6.6.2 The maximal dose (hotspot) should be less than 105% of the dose. 
6.6.3 Acceptable deviation (e.g., to meet the critical organ constraints) will be if 
the 90-95% isodose line covers the 100% of the PTV volume or if 95% isodose 
line covers 95% of the PTV volume. 
6.6.4 It may be impossible to account for all anatomic tumor to normal structure 
configurations and scenarios.  There may be scenarios in which normal structure 
constraints cannot be achieved (for example edema or gross tumor that contacts 
these structures like medial temporal tumors).  As per standard of care 
guidelines, all attempts to spare normal structures (for example decrease 
CTV/PTV) should be attempted.   
 


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7.0  DRUG THERAPY 
Treatment must begin ≥ 3 weeks and ≤ 6 weeks after (the last) surgery.  This will 
follow the standard Stupp regimen with optional PCP prophylaxis.  These are 
guidelines for the standard concurrent and adjuvant temozolomide.  The decision 
and timing of temozolomide dose maintenance, escalation and/or reduction will 
be at the discretion of the treating physician since this is not a study related 
question. 
 
7.1 
TMZ During Concomitant RT 
7.1.1 TMZ will be administered continuously starting the night before the first 
day to the last day of radiation at a daily oral dose of 75 mg/m2 for a maximum of 
49 days.  The drug will be administered orally at night.  Please note TMZ can be 
started within 24 hours of first fraction of Radiation Treatment (± 1 day of RT). 
7.1.2 The dose will be determined using actual body surface area (BSA) as 
calculated in square meters at the beginning of the concomitant treatment.  The 
BSA will be calculated from the height and weight obtained at the pretreatment 
history and physical.  Capsules of TMZ are available in 5, 20, 100, 140, 180, and 
250 mg.  The daily dose will be delivered within ± 10% of target dose determined 
by BSA. 
7.1.3 Patients will be instructed to swallow the capsules whole, in rapid 
succession, without chewing them.  If vomiting occurs during the course of 
treatment, no re-dosing of the patient is allowed before the next scheduled dose.  
The capsules should be taken at least two hours after last food consumption with 
no food consumption for at least 1 hour after TMZ administration.  Nightly 
administration just before bedtime is conventionally recommended, starting on 
the night prior to initiating RT.  Any dose that is missed will not be made up. 
7.1.4 During treatment with RT and TMZ a CBC with differential and a CMP 
including Liver Function Tests will be obtained every 2 weeks.  The patient will 
also be evaluated for toxicities weekly. 
7.1.5 Prophylaxis with a 5-HT3 antagonist is recommended prior to 
administration of TMZ doses and should be administered orally 30 to 60 minutes 
before TMZ treatment.  In the unusual event that a 5-HT3 antagonist is not 
adequate to control nausea, additional use of Compazine, Phenergan, or 
metoclopramide may be utilized at the discretion of the treating physician. 
7.1.6 Pneumocystis carinii prophylaxis is optional during the radiation phase. 
7.1.7 If significant toxicity from concomitant treatment persists over 8 weeks 
from the time of completion of the radiation, the patient will be removed from 
protocol treatment. 
 
7.2 Post-Radiation TMZ  
7.2.1 TMZ will be administered orally once per day for 5 consecutive days (days 
1-5) of a 28 day cycle.  The starting dose for the first cycle will be 150 mg/m2 / 
day, with a single dose escalation to 200 mg/m2 / day in subsequent cycles if no 
treatment-related adverse events > grade 2 are noted. (TMZ regimen can be 
switched to TMZ 75 mg/m2 / day on days 1-21 of a 28 day cycle at the treating 
physician’s discretion.) 


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7.2.2 The start of the first cycle will be scheduled 28 days ± 3 days after the last 
day of radiotherapy.  The start of all subsequent cycles (2-12) will be scheduled 
every 4 weeks (28 days ± 3 days) after the first daily dose of TMZ of the 
preceding cycle. 
7.2.3 The dose will be determined using the BSA calculated at the beginning of 
each treatment cycle.  The BSA will be calculated from the height obtained at the 
pretreatment visit and from the weight obtained at the visit prior to each cycle 
start.  Capsules of TMZ are available in 5, 20, 100, 140, 180, and 250 mg.  The 
daily dose will be delivered within ± 10% of target dose determined by BSA.  The 
exact dose administered should be recorded.  Each daily dose should be given 
with the least number of capsules. 
7.2.4 Patients will be instructed to fast at least 2 hours before and 1 hour after 
TMZ administration.  Water is allowed during the fast period.  Patients will be 
instructed to swallow the capsules whole, in rapid succession, without chewing 
them.  Treatment should be given at night.  Any dose that is missed will not be 
made up. 
7.2.5 Prior to each treatment cycle with TMZ a complete blood count (CBC) with 
differential and CMP including Liver Function Tests, a history and physical with 
neurological exam, steroid documentation, and toxicity assessment is to be done 
within 7 days prior to start of each cycle.  Prior to cycle 1 and then every 2-3 
months until the end of Adjuvant TMZ a brain MRI with contrast (or brain CT with 
contrast, if MRI is contraindicated) will be obtained. 
7.2.6 If vomiting occurs during the course of treatment, no re-dosing of the 
patient is allowed before the next scheduled dose. 
7.2.7 Antiemetic prophylaxis with a 5-HT3 antagonist is strongly recommended 
and should be administered 30 to 60 minutes before TMZ administration.  See 
Section 7.1.5. 
7.2.8 Pneumocystis carinii prophylaxis is optional during the adjuvant phase. 
7.2.9 Duration of Treatment 
Patients will be treated with post-radiation TMZ for 6 cycles unless there is 
evidence of tumor progression or treatment-related toxicity.  At the completion of 
6 cycles, patients may receive up to an additional 6 cycles of treatment 
(therefore, a maximum of 12 cycles) if treatment has been well tolerated and at 
least one of the following criteria demonstrating continued benefit is met: 
 Serial MRI studies show continued tumor response as evidenced by no 
increase in tumor size. 
 The 
patient 
demonstrates 
progressive 
improvement 
in 
overall 
performance status. 
 The patient demonstrates clinical improvement by improvement in 
neurologic function. 
 The patient demonstrates ongoing treatment benefit by a decreasing 
requirement of corticosteroids. 
7.2.10  Tumor Treating Fields can be used after radiation therapy at the 
discretion of the treating physician. 
 
7.3 
TMZ Agent Information (Temozolomide, Temodar, Temodal) 


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Please refer to the package insert for comprehensive information. 
7.3.1 Formulation 
Other Names: methazolastone; TMZ is supplied in white opaque, preservative-
free, two-piece, hard gelatin capsules of the following p.o. dosage strengths: 5 
mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg.  Each capsule contains drug 
substance in combination with lactose, anhydrous NF, colloidal silicon dioxide 
NF, sodium starch glycolate NF, tartaric acid NF, and stearic acid NF.  The 
capsule shells contain gelatin NF, titanium dioxide USP, and sodium lautyl 
sulfate NF. 
7.3.2 Mode of Action 
Alkylating agent of imidazotetrazinone class. 
7.3.3 Storage and Stability 
The capsules are packaged in amber glass bottles and should be stored at 25°C.  
Temperature excursions between 15 and 30°C are permissible.  Refer to the 
commercially labeled bottles for expiration dating. 
7.3.4 Pharmacokinetics 
TMZ is rapidly and completely absorbed after oral administration; peak plasma 
concentrations occur in 1 hour.  Food reduces the rate and extent of TMZ 
absorption.  Mean peak plasma concentration and AUC decreased by 32% and 
9%, respectively, and Tmax increased 2-fold (from 1.1 to 2.25 hours) when TMZ 
was administered after a modified high-fat breakfast. 
 
TMZ is rapidly eliminated with a mean elimination half-life of 1.8 hours and 
exhibits linear kinetics over the therapeutic dosing range.  TMZ has a mean 
apparent volume of distribution of 0.4 L/kg (%CV=13%).  It is weakly bound to 
human plasma proteins; the mean percent bound of drug-related total 
radioactivity is 15%. 
7.3.5 Metabolism and Elimination 
TMZ is spontaneously hydrolyzed at physiologic pH to the active species, 3-
methyl-(triazen-1-yl)imidazole-4-carboxamide 
(MTIC) 
and 
to 
TMZ 
acid 
metabolite.  MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide 
(AIC), which is known to be an intermediate in purine and nucleic acid 
biosynthesis and to methylhydrazine, which is believed to be the active alkylating 
species.  Cytochrome P450 enzymes play only a minor role in the metabolism of 
TMZ and MTIC.  Relative to the AUC of TMZ, the exposure to MTIC and ACI is 
2.4% and 23%, respectively.  About 38% of the administered TMZ total 
radioactive dose is recovered over 7 days; 37.7% in urine and 0.8% in feces.  
The majority of the recovery of radioactivity in urine is as unchanged TMZ 
(5.6%), AIC (12%), TMZ acid metabolite (2.3%), and unidentified polar 
metabolites(s) (17%).  Overall clearance of TMZ is about 5.5 L/hr/m2. 
7.3.6 Special Populations 
7.3.6.1 Creatinine Clearance: Population pharmacokinetic analysis 
indicates that creatinine clearance over the range of 36-130 mL/min/m2 
has no effect on the clearance of TMZ after oral administration.  The 
pharmacokinetics of TMZ have not been studied in patients with severely 
impaired renal function (CLcr < 36 mL/min/m2).  Caution should be 


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exercised when TMZ is administered to patients with severe renal 
impairment.  TMZ has not been studied in patients on dialysis. 
7.3.6.2 Hepatically Impaired Patients: In a pharmacokinetic study, the 
pharmacokinetics of TMZ in patients with mild to moderate hepatic 
impairment (Child’s-Pugh Class I-II) were similar to those observed in 
patients with normal hepatic function.  Caution should be exercised when 
TMZ is administered to patients with severe hepatic impairment. 
7.3.6.3 Gender: Population pharmacokinetic analysis indicates that 
women have an approximately 5% lower clearance (adjusted for body 
surface area) for TMZ than men.  Women have higher incidences of grade 
4 neutropenia and thrombocytopenia in the first cycle of therapy than men. 
7.3.6.4 Age: Population pharmacokinetic analysis indicates that age 
(range 19-78 years) has no influence on the pharmacokinetics of TMZ.  In 
the anaplastic astrocytoma study population, patients 70 years of age or 
older had a higher incidence of grade 4 neutropenia and grade 4 
thrombocytopenia in the first cycle of therapy than patients under 70 years 
of age.  In the entire safety database, however, there did not appear to be 
a higher incidence in patients 70 years of age or older. 
7.3.7 Drug-Drug Interactions 
In a multiple dose study, administration of TMZ with ranitidine did not change the 
Cmax or AUC values for TMZ or MTIC.  Population analysis indicates that 
administration of valproic acid decreases the clearance of TMZ by about 5%.  
The clinical implication of this effect is not known.  Population analysis failed to 
demonstrate any influence of coadministered dexamethasone, prochlorperazine, 
phenytoin, 
carbamazepine, 
ondansetron, 
H2-receptor 
antagonists, 
or 
phenobarbital on the clearance of orally administered TMZ. 
7.3.8 TMZ is potentially mutagenic and should be handled with appropriate 
precautions by both staff and patients.  Capsules should not be opened.  If 
capsules are accidentally opened or damaged, rigorous precautions should be 
taken with the capsule contents to avoid inhalation or contact with the skin or 
mucous membranes.  Procedures for proper handling and disposal of anticancer 
drugs should be considered. 
7.3.9 Contraindications 
TMZ is contraindicated in patients who have a history of a hypersensitivity 
reaction to any of its components or to DTIC. 
7.3.10 Pregnancy Category D 
TMZ may cause fetal harm when administered to a pregnant woman.  There are 
no adequate and well-controlled studies in pregnant women.  If this drug is used 
during pregnancy, or if the patient becomes pregnant while taking this drug, the 
patient should be apprised of the potential hazard to the fetus.  Women of 
childbearing potential should be advised to avoid becoming pregnant during 
therapy with TMZ. 
 
Treatment of a man with TMZ may increase the risk of birth defects if he causes 
a woman to become pregnant while he is taking TMZ.  Men treated with TMZ 
may have difficulty causing a woman to become pregnant after their treatment is 


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completed.  Men receiving TMZ should be directed to use effective contraception 
while they are being treated.  There is insufficient data to know what the risk of 
subsequent problems with fertility will be.  Similarly, women who are treated with 
TMZ may have difficulty becoming pregnant in the future and may at be at 
increased risk of having children with birth defects.  There is insufficient evidence 
to determine what the risk of these complications will be. 
7.3.11 Supply 
Commercially available. 
 
7.4 
Dose Modifications 
7.4.1 TMZ 
7.4.1.1 TMZ During Concomitant RT 
No dose reduction will be made, but delay or discontinuation of TMZ 
administration will be decided bi-weekly according to hematologic and 
non-hematologic adverse events (AEs), as specified below. 
 
If the administration of TMZ has to be interrupted, the radiotherapy will 
proceed normally.  Missed doses of TMZ will not be made up at the end of 
radiotherapy.  The total number of days and total dose of TMZ will be 
recorded. 
 
If one or more of the following are observed: 
 ANC < 1.0 x 109/L 
 Platelet count < 75 x 109/L 
 Grade 3 non-hematologic AE (except alopecia, nausea and 
vomiting while on maximal antiemetic therapy, fatigue, DVT and 
PE) 
 
Then treatment with concomitant TMZ will be withheld until all of the 
following conditions are met: 
 ANC ≥ 1.0 x 109/L 
 Platelet count ≥ 75 x 109/L 
 Grade ≤ 1 non-hematologic AE (except alopecia, nausea and 
vomiting, fatigue, DVT and PE) 
 
In case of hematologic AE as defined above, a complete blood count 
(CBC) with differential should be performed at least twice weekly.  In case 
of non-hematologic AE, the patient should be assessed at least weekly 
with relevant laboratory test(s).  As soon as all of the above conditions are 
met, the administration of TMZ will resume at the same dose as used 
initially. 
 
If one or more of the following are observed: 
 ANC < 0.5 x 109/L (Grade 4) 
 Platelet count < 25 x 109/L (Grade 4) 


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 Grade 4 non-hematologic AE (except alopecia, nausea and 
vomiting, unless the patient has failed maximal antiemetic 
therapy, fatigue, DVT and PE) 
 
Then treatment with concomitant TMZ should be stopped. 
 
AE 
Value 
Grade 
Action 
ANC 
< 1.0 – 0.5 x 109/L 
3 
Delay TMZ until: 
- ANC ≥ 1.0 x 109/L 
- Platelet ≥ 75 x 
109/L 
- Non-hem AE ≤ 1  
Platelet Count 
< 75 – 25 x 109/L 
2, 3 
Non-hematologic 
(except alopecia, 
nausea/vomiting 
unless on maximal 
antiemetic therapy) 
N/A 
3 
 
ANC 
< 0.5 x 109/L 
4 
Stop concomitant 
TMZ 
Platelet count 
< 25 x 109/L 
4 
Non-hematologic 
(except alopecia, 
nausea/vomiting) 
N/A 
4 
 
7.4.1.1.1  Concomitant TMZ, if RT is interrupted 
If radiotherapy has to be temporarily interrupted for technical or 
medical reasons unrelated to the TMZ administration, then 
treatment with daily TMZ should also stop.  If radiotherapy has to 
be permanently interrupted then treatment with daily TMZ should 
stop.  TMZ can resume with resumption of radiotherapy.  TMZ can 
also resume with the initiation of the adjuvant phase of treatment. 
 
If the duration of radiotherapy exceeds 7 weeks, then concomitant 
treatment with TMZ should be stopped after 49 days of TMZ 
treatment. 
7.4.1.2  Post-Radiation (Adjuvant) TMZ 
Dosing is based on adverse events (AEs) during the prior treatment cycle.  
If multiple AEs are seen, the dose administered should be based on the 
dose reduction required for the most severe grade of any single AE. 
 
 
 
Dose Level 
TMZ Dose, mg/m2 / day 
Remarks 
-2 
100 
Reduction if prior AE grade 3 
event attributable as probably 
related to Temodar, persisting > 
7 days despite optimal medical 
management, except DVT or PE 
-1 
125 
Reduction if prior AE grade 3 


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event attributable as probably 
related to Temodar, persisting > 
7 days despite optimal medical 
management, except DVT or PE 
0 
150 
Starting dose cycle 1 (adjuvant) 
+1 
200 
Escalated dose at cycle 2, for 
cycles 2-12 in absence of AE 
 
7.4.1.2.1  Delay 
Within 7 days of the start of a new cycle, ANC ≥ 1.5 x 109/L, platelet 
count ≥ 100 x 109/L and all treatment-related grade 3 or 4 non-
hematologic AEs (except alopecia, nausea, vomiting, fatigue, DVT 
and PE) must have resolved (to grade ≤ 1). 
 
If AEs persists, treatment should be delayed by 1 week for up to 4 
consecutive weeks.  If, after 4 weeks of delay, all AEs have still not 
resolved: then any further adjuvant treatment with TMZ should be 
stopped. 
7.4.1.2.2  Dose escalation 
If, during the first cycle, all non-hematologic AEs observed were 
grade ≤ 2 (except alopecia, nausea and vomiting) and with platelets 
≥ 100 x 109/L and ANC ≥ 1.5 x109/L: then the TMZ dose should be 
escalated to dose level 1 and this dose should be used as the 
starting dose for subsequent cycles.  If treatment after cycle 1 has 
to be delayed because of ongoing non-hematologic AEs of grade ≥ 
2, then no escalation is possible.  If the dose was not escalated at 
cycle 2, then the dose should not be escalated in further cycles (3-
12). 
7.4.1.2.3  Dose reduction 
If any non-hematologic AE observed was grade > 2 (except 
alopecia, nausea, vomiting, fatigue, DVT and PE) and/or if platelets 
< 50 x 109/L and/or ANC < 1 x 109/L, then the dose should be 
reduced by one dose level.  For patients who would require dose 
reductions to a dose level < 100 mg/m2 / day, TMZ will be stopped.  
Also, if any of the same non-hematologic grade 3 AE recurs (except 
alopecia, nausea, vomiting, and fatigue) after reduction for that AE, 
then TMZ will be stopped. 
 
If any treatment-related non-hematologic AE observed was grade 4 
(except alopecia, nausea, vomiting, and fatigue) then adjuvant TMZ 
treatment should be stopped. 
7.4.1.2.4  Subsequent cycles 
Any dose reductions of TMZ will be determined according to (1) 
non-hematologic AE during the preceding treatment cycle, as well 
as (2) the nadir (lowest/worst) ANC and platelet counts observed.  


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No dose escalation should be attempted.  The same dose 
reductions as for the second cycle should be applied. 
7.4.1.2.5  Important 
If the dose was reduced or delayed for adverse events, there will be 
no dose escalation.  The reason(s) for the dose reduction and/or 
delay must be documented. 


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Summary of Dose Modification or Discontinuation During Post-Radiation TMZ 
 
Hematologic AE on Day 1 of Each Cycle (within 7 days* before starting) 
AE 
Delay 
ANC < 1.5 x 109/L 
 
and/or 
 
Platelet count < 100 x 109/L 
Delay in 1 week increments up to 4 weeks 
until all resolved.  If unresolved after 4 
weeks then stop. If resolved, dose 
delay/reductions 
based 
on 
non-
hematologic AEs are applicable.  If 
treatment has to be delayed for AEs, then 
no escalation is possible. 
* See Section 7.2.5 for timing of evaluations prior to starting each adjuvant cycle. 
 
Non-Hematological AE (except for alopecia, nausea, vomiting,fatigue, DVT and 
PE) on Day 1 of Each Cycle (within 7 days* before starting) 
Grade 
Delay 
2-3 
Delay in 1 week increments up to 4 weeks until all resolved (to grade ≤ 
1).  If unresolved after 4 weeks, then stop.  If resolved, dose 
delay/reductions based on ANC and platelets are applicable.  If 
treatment has to be delayed for AEs, then no escalation is possible. 
* See Section 7.2.5 for timing of evaluations prior to starting each adjuvant cycle. 
 
Worst Non-Hematologic AE ( except alopecia, nausea, vomiting, fatigue, DVT and 
PE) During the Previous Cycles 
Grade 
Dose Modification 
0-2 
No dose modifications for non-hematologic AEs.  Dose escalations (only for 
cycle 2) or reductions based on ANC and platelet counts are applicable. 
3 
Reduce by one dose level (except alopecia, nausea, vomiting, fatigue, DVT 
and PE).  Dose modifications (escalations or reductions) based on ANC and 
platelet counts are not applicable.  No further escalation is possible.  If the 
same non-hematologic grade 3 AE recurs (except alopecia, nausea, 
vomiting, and fatigue) after reduction for that AE, then stop. 
4 
Stop (except alopecia, nausea, vomiting, and fatigue).  Dose modifications 
(escalations or reductions) based on ANC and platelet counts are not 
applicable. 
 
Nadir Values 
Platelets 
ANC 
 
≥ 100 x 109/L 
50 – 99 x 109/L 
< 50 x 109/L 
≥ 1.5 x 109/L 
Escalation to 
DL 1  
(cycle 2 only) 
Dose 
unchanged 
Reduce by 1 
dose level 
≥ 1 & < 1.5 x 109/L 
Dose 
unchanged 
Dose 
unchanged 
Reduce by 1 
dose level 
< 1 x 109/L 
Reduce by 1 
dose level 
Reduce by 1 
dose level 
Reduce by 1 
dose level 
 


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7.5 
Data Safety Monitoring and Adverse Events 
7.5.1 Data and Safety Monitoring / Quality Assurance Committee  
This study will be governed by the UMGCC Data Safety Mointoring / Quality 
Assurance Committee (DSMQAC).  The study will be sent to the DSMQAC for a 
mandatory interim review after the first 6 patients have been accrued.  Once the 
DSMQAC has reviewed and approved the initial 6 patients on the study, 41 
additional patients will be enrolled.  The study will be reviewed by the DSMQAC 
on an annual basis and a report will be uploaded in the continuing review 
submitted to the Institutional Review Board (IRB). 
7.5.2 Anticipated Toxicities 
All anticipated toxicities are listed in the informed consent document. 
7.5.3 Toxicity Reporting 
The research team and the treating physicians/PI will review the toxicities and 
record them in Oncore.  Attribution of toxicity to protocol and clinical relevance 
will be reviewed. 
 
If a dose limiting toxicity or other significant medical event is unexpected and 
probably related to study treatment, then it will be submitted to the IRB via the 
Reportable New Information (RNI) guidelines.  All AE’s entered into Oncore will 
be submitted for review on an annual basis. 
 
Patients that are withdrawn from protocol treatment will be followed for adverse 
events for 30 days after last dose of TMZ or Radiation Treatment. 
7.5.4 Grading Toxicities 
The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for 
AE reporting. 
 
8.0  SURGERY AND OTHER THERAPY 
 
8.1 
Surgery 
8.1.1 All patients require histological confirmed WHO grade IV tumor.  Thus, at 
the minimum, a biopsy is required. 
8.1.2 Decision for surgical resection is at the discretion of the treating surgeon 
since this is the standard of care.  Multiple attempts at resection are allowed.  
Other procedures such as shunt placement, abscess drainage, wound repair, etc 
will be allowed at the discretion of the surgeon. 
 
8.2 
Permitted Supportive Therapy 
All supportive therapy for optimal medical care will be given during the study 
period at the discretion of the attending physician(s) within the parameters of the 
protocol and documented on each site’s source documents as concomitant 
medication. 
8.2.1 Anticonvulsants: Anticonvulsants may be used as clinically indicated.  
Doses at study entry and at specific time points of the treatment must be 


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recorded.  The use of hepatic cytochrome p450 enzyme inducing anticonvulsants 
does NOT change dosing of TMZ. 
8.2.2 Corticosteroids: Corticosteroids may be administered at the treating 
physician’s discretion.  Doses at study entry and at specific time points of the 
treatment must be recorded. 
8.2.3 Antiemetics: Prophylactic antiemetics may be administered at the treating 
physician’s discretion. 
8.2.4 Pneumocystic Carinii Prophylaxis: Both corticosteroid therapy and 
continuous TMZ therapy induce lymphocytopenia.  Patients receiving any of 
these drugs or both concomitantly are at an increased risk for opportunistic 
infections.  Therefore, a prophylaxis against P. carinii pneumonia is required for 
all patients receiving TMZ during radiotherapy: trimethoprim-sulfamethoxazole 
(Bactrim forte®, Bactrim DS®) 1 tablet 3 times per week or monthly pentamidine 
inhalations (300 mg via aerosol monthly) or dapsone 100 mg po each day 
(except in patients with G6-PD deficiency).  Prophylaxis is recommended to 
continue for the duration of radiotherapy, regardless of the lymphocyte count.  
After completion of the chemoradiation, patients with a lymphocyte count < 
500/mm3 should have CD4 quantification.  If the CD4 is < 200, then prophylaxis 
is recommended to continue and the CD4 should be quantified on a monthly 
basis.  If the lymphocyte count is ≥ 500 or the CD4 is > 200, then prophylaxis can 
be stopped. 
 
8.3 
Non-Permitted Supportive Therapy 
8.3.1 Growth factors are not permitted to induce elevations in neutrophil count 
for the purposes of: (1) administration of TMZ on the scheduled dosing interval; 
(2) allowing treatment with TMZ at a higher dose; or (3) avoiding interruption of 
the treatment during concomitant radiotherapy. 
8.3.2 No other investigational drugs will be allowed during the trial. 
8.3.3 Other types of chemotherapy, and immunotherapy or biologic therapy 
must not be used.  Further, additional stereotactic boost radiotherapy is not 
allowed.  If any of these treatments are required, the patient will be off protocol.  
All further therapy is at the treating physicians discretion, but should be recorded. 
 
 
9.0  STATISTICAL CONSIDERATIONS 
 
This study will enroll 47 patients total.  After the first 6 patients have been enrolled a 
mandatory review will take place.  Should the study be approved to proceed, 41 
additional patients will be enrolled. 
 
The primary endpoint for this trial and the one that is factored into the power analysis is 
the proportion of patients that have distant metastases at 1 year.  The historical rate of 
distant metastases is 30% and we anticipate that this rate will be lowered to 10% 
among the patients accrued to this trial.  We plan to accrue 37 patients to achieve 80% 
power to conclude that the rate is ≤ 10% given that the true rate doesn’t exceed 16%.  
Given that 6 or fewer patients experience distant metastases during the first year, we 


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will accept the research hypothesis that the rate ≤ 10%.  If 7 or more patients have 
distant metastases within the first year, we will instead not reject the null hypothesis that 
the experimental rate is no different from the historical rate; we will have 95% 
confidence to make this determination.  To account for patients that fail to provide 
enough follow-up, or are withdrawn from the study, we plan to accrue 25% more 
patients that required for a total of 47 patients to be enrolled. 


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10.0  REFERENCES 
                                                          
1 Bruce JN. Glioblastoma multiforme. Medscape 2009. Accessed Apr 4 2011: 
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2 Hou LC, Veeravagu A, Hsu AR, and Tse VCK. Recurrent glioblastoma multiforme: A 
review of natural history and management options. Neurosurg Focus 2006; 20 (4).  
 
3 Stupp R, Hegl EM, Mason WP, et al. Effects of radiotherapy with concomitant and 
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66. 
 
4 Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and 
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5 Walker MD, Alexander E Jr, Hunt WE, et al. Evaluation of BCNU and/or radiotherapy 
in the treatment of anaplastic gliomas: A cooperative clinical trial. J Neurosurg 1978; 49: 
333-43.  
 
6 Walker MD, Strike TA, and Sheline GE. An analysis of dose-effect relationship in the 
radiotherapy of malignant glioma. Int J Radiat Oncol Biol Phys 1979; 5: 1725-31.  
 
7 DeSchryver A, Greitz T, Forsby N, et al: Localized shaped field radiotherapy of 
malignant glioblastoma multiforme. Int J Radiat Oncol Biol Phys 1976; 1:713-16. 
 
8 Hochberg FH, Pruitt A: Assumptions in the radiotherapy of glioblastoma. Neurology 
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9 Brandsma D, Stalpers L, Taal W, et al. Clinical features, mechanisms, and 
management of pseudoprogression in malignant gliomas. Lancet Oncol 2008; 9: 453-
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10 Chan JL, Lee SW, Fraass BA, et al. Survival and failure patterns of high-grade 
gliomas after three-dimensional conformal radiotherapy. J Clin Oncol 2002; 20: 1635-42 
 
11 Sharma RR, Singh DP, Pathak A, et al. Local control of high-grade gliomas with 
limited volume irradiation versus whole brain irradiation. Neurology India 2003; 51: 512-
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12 Wallner KE, Galicich JH, Krol G, et al: Patterns of failure following treatment for 
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13 Lee S, Fraass BA, Herbort K, et al: Patterns of failure following high dose 3-D 
conformal radiotherapy for high grade astrocytomas: A quantitative dosimetric study. Int 
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14 Liang BC, Thornton AF, Sandler HM, et al: Malignant astrocytomas: Focal tumor 
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15 Buckner JC. Factors influencing survival in high-grade gliomas. Semin Oncol 2003; 
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16 Curran WJ Jr, Scott CB, Horton J, et al. Recursive partitioning analysis of prognostic 
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17 DeAngelis LM. Brain tumors. N Engl J Med 2001; 344:114-23. 
 
18 Stupp R, Dietrich P-Y, Ostermann Kraljevic S, et al. Promising survival for patients 
with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus 
TMZ followed by adjuvant TMZ. J Clin Oncol 2002; 20:1375-82. 
 
19 Brandes AA, Tosoni A, Franceschi E, et al. Recurrence pattern after TMZ 
concomitant with and adjuvant to radiotherapy in newly diagnosed patients with 
glioblastoma: Correlation with MGMT promoter methylation status. J Clin Oncol 2009; 
27:1275-1279. 
 
20 Peiffer J, Kleihues P. Hans-Joachim Scherer (1906-1945), pioneer in glioma 
research.  Brain Pathol 1999;9(2):241-5. 
 
21 Carrier F, Diss E, Nalabothula, Kwok Y.  The histone deacetylase inhibitor vorinostat 
induces hyper-radiosensitivity (HRS) in p53 wild type glioblastoma cells.  Int J Radiat 
Oncol Biol Phys 2011;81:S747. 
 
22 Antonadou D, Paraskevaidis M, Sarris G, et al.  Phase II randomized trial of 
temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin 
Oncol 2002;20:3644-3650. 
 
23 Verger E, Gil M, Yaya R, et al. Temozolomide and concomitant whole brain 
radiotherapy in patients with brain metastases: a phase II randomized trial. Int J Radiat 
Oncol Biol Phys 2005;61:185-194.