Clinical trial NCT01120639
Conditions: Glioblastoma Cancer of Brain and Nervous System Glioblastoma Multiforme
Sponsor: Stanford University
Start date: 2010-04-01; Completion date: 2020-11-15
Enrollment: 30 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to investigate the safety and effectiveness of a combination treatment for glioblastoma multiforme utilizing radiotherapy plus the FDA-approved chemotherapy drug temozolomide

Detailed description:
Primary Objective: To determine the maximum tolerated dose (MTD), based on acute CNS toxicity at 30 days, of hypofractionated radiotherapy given in 5 fractions with temozolomide for the treatment of glioblastoma multiforme.

Secondary Objectives:

1. Assess the short- and long-term adverse effects.
2. Determine the radiographic response rate.
3. Determine the overall survival rate.
4. Assess quality of life during treatment

To determine the maximum tolerated dose (MTD) of hypofractionated (5 fractions) radiotherapy with temozolomide for the treatment of glioblastoma multiforme, patients will be evaluated by a multi-disciplinary team composed of radiation oncologists, neurosurgeons, and neuro-oncologists to assess for their eligibility. Patient's oncologic history, presenting symptoms, physical examination, pathology, and imaging studies will be reviewed. Patients will be evaluated for surgical candidacy and resectability. Patients who are surgical candidates will undergo a surgical resection prior to radiotherapy. Patients whose tumors are unresectable or are not good surgical candidates will undergo a biopsy for tissue diagnosis. Radiation will be delivered in five fractions.

Arms: arm 1: Hypofractionated stereotactic radiosurgery with concurrent temozolomide, stratified by Planning Target Volume (PTV) \< 60 cm³ vs 60 to 150 cm³. arm 2: Hypofractionated stereotactic radiosurgery with concurrent temozolomide, stratified by Planning Target Volume (PTV) \< 60 cm³ vs 60 to 150 cm³. arm 3: Hypofractionated stereotactic radiosurgery with concurrent temozolomide, stratified by Planning Target Volume (PTV) \< 60 cm³ vs 60 to 150 cm³. arm 4: Hypofractionated stereotactic radiosurgery with concurrent temozolomide, stratified by Planning Target Volume (PTV) \< 60 cm³ vs 60 to 150 cm³.
Interventions: intervention 1: Temozolomide intervention 2: Stereotactic Radiosurgery (SRS)
Intervention descriptions: intervention 1: 75 mg/m²/day oral, administered concurrently with radiotherapy and as adjuvant therapy. intervention 2: Standard of care therapeutic radiotherapy administrated at 25, 30, 35, or 40 Gray (Gy)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
A PHASE I/II TRIAL OF TEMOZOLOMIDE AND HYPOFRACTIONATED 
RADIOTHERAPY IN THE TREATMENT OF SUPRATENTORIAL GLIOBLASTOMA 
MULTIFORME 
NCT01120639 
DATE: 03-Dec-2015 
 
 
Coordinating Center: 
Stanford Cancer Center 
 
875 Blake Wilbur Drive  
 
Stanford, CA 94305 
 
 
Protocol Directors:  
Scott G. Soltys, M.D. 
 
 
 
 
Stanford Cancer Center 
 
 
 
 
875 Blake Wilbur Drive 
 
 
 
 
Stanford, CA 94305-5847 
 
 
 
 
sgsoltys@stanford.edu 
 
 
 
 
 
Clara Y. Choi, M.D., Ph.D. 
 
 
 
 
300 Pasteur Drive 
 
 
 
 
Stanford, CA 94035-5327 
 
 
 
 
cyhchoi@stanford.edu  
 
Co-Investigators: 
 
Iris C. Gibbs, M.D. 
 
 
 
 
Stanford Cancer Center 
 
 
 
 
875 Blake Wilbur Drive 
 
 
 
 
Stanford, CA 94305-5847 
 
 
 
 
dover@stanford.edu  
 
 
 
 
 
Steven D. Chang, M.D. 
 
 
 
 
300 Pasteur Drive R225 
 
 
 
 
Stanford, CA 94305-5327 
 
 
 
 
sdchang@stanford.edu 
 
 
 
 
 
Griffith Harsh, M.D. 
 
 
 
 
300 Pasteur Drive 
 
 
 
 
Stanford, CA 94035-5327 
 
 
 
 
gharsh@stanford.edu 
 
  
 
 
 
Lawrence Recht, M.D. 
 
875 Blake Wilbur Drive. 
 
Rm CC-221 
 
Stanford, CA 94305-5826 
 
lrecht@stanford.edu 
 


 
 
 
Biostatistician: 
Alex McMillan, Ph.D. 
Health Research & Policy (Redwood Building) 
Room T160A 
259 Campus Drive 
Stanford, CA 94305-5327 
Alex.McMillan@stanford.edu 
 
 
Study Coordinator: 
Jacob Wynne 
875 Blake Wilbur Drive 
Stanford, CA 94305 
jwynne@stanford.edu  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Protocol Type / Version # / Version Date: 
Revision / Version 1.7 /3Dec2015 
 
 
 


 
 
TABLE OF CONTENTS 
 
 
 
Page 
PROTOCOL SYNOPSIS ..............................................................................................................5 
SCHEMA ........................................................................................................................................8 
LIST OF ABBREVIATIONS .......................................................................................................9 
 
 
1. OBJECTIVES ........................................................................................................................10 
1.1.Primary Objectives.............................................................................................................10 
1.2.Secondary Objectives.........................................................................................................10 
2. BACKGROUND ....................................................................................................................10 
2.1.Glioblastoma Multiforme...................................................................................................10 
2.2.Hypofractionated Radiotherapy .........................................................................................10 
2.3.Temozolomide ...................................................................................................................12 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES .........................12 
3.1.Inclusion Criteria ...............................................................................................................12 
3.2.Exclusion Criteria ..............................................................................................................13 
3.3.Informed Consent Process .................................................................................................14 
4. TREATMENT PLAN ............................................................................................................14 
4.1.Pretreatment Evaluation .....................................................................................................14 
4.2.Surgical Treatment .............................................................................................................14 
4.3.Radiation Therapy ..............................................................................................................14 
4.4.Drug Therapy .....................................................................................................................17 
4.5.General Concomitant Medication and Supportive Care Guidelines ..................................18 
4.6.Duration of Therapy ...........................................................................................................19 
4.7.Duration of Follow Up .......................................................................................................19 
4.8.Criteria for Removal from Study .......................................................................................20 
4.9.Alternatives ........................................................................................................................21 
4.10.Compensation ..................................................................................................................21 
5. DOSING DELAYS/DOSE MODIFICATIONS ..................................................................21 
6. ADVERSE EVENTS AND REPORTING PROCEDURES ..............................................21 
6.1.Potential Adverse Events ...................................................................................................21 
6.2.Adverse Event Reporting ...................................................................................................23 
7. CORRELATIVE/SPECIAL STUDIES ...............................................................................24 
8. STUDY CALENDAR ............................................................................................................24 
9. MEASUREMENT OF EFFECT ..........................................................................................25 
10.1.Anti-tumor Effect .............................................................................................................25 
10.2.Other Response Parameters .............................................................................................26 
10. DATA REPORTING/REGULATORY CONSIDERATIONS ..........................................26 
11.1.Monitoring Plan ...............................................................................................................26 
11.2.Stopping Rules .................................................................................................................26 
11.4.Confidentiality .................................................................................................................27 
11. STATISTICAL CONSIDERATIONS .................................................................................27 
12.1.Endpoints .........................................................................................................................27 


 
 
12.4.Sample Size ......................................................................................................................27 
 
REFERENCES .............................................................................................................................28 
 
APPENDICES 
 
A. Participant Eligibility Checklist  
 
B. Participant Initial Consultation and Follow-up Forms 
 
C. Informed Consent Form 
 


 
 
PROTOCOL SYNOPSIS 
 
TITLE 
A Phase I/II Trial Of Temozolomide And 
Hypofractionated Radiotherapy In The 
Treatment Of Supratentorial Glioblastoma 
Multiforme 
STUDY PHASE 
I/II 
INDICATION 
Newly diagnosed, histologically confirmed 
supratentorial GBM. 
PRIMARY OBJECTVES 
Phase I - Primary Objective 
Determine the maximum tolerated dose (MTD) 
of hypofractionated radiotherapy given in 5 
fractions with temozolomide for the treatment 
of glioblastoma multiforme.  
 
SECONDARY OBJECTIVES 
Determine the short- and long-term adverse 
effects. 
Determine the radiographic response rate.   
Determine the overall survival rate. 
Perform patterns of failure analysis. 
Assess quality of life during treatment. 
HYPOTHESES 
Five fraction stereotactic radiosurgery (SRS) 
with concurrent temozolomide will be well-
tolerated; the duration of radiotherapy can 
safely be shortened to 5 treatments without 
compromising the local control or overall 
survival rates. 
STUDY DESIGN 
Phase I: The MTD for five-fraction SRS 
concurrent 
with 
temozolomide 
will 
be 
determined using a 3+3 study design.   
 
PRIMARY ENDPOINTS AND 
SECONDARY ENDPOINTS 
Phase I Primary endpoint 
The MTD and DLT of hypofractionated 
radiotherapy with temozolomide will be 
determined. 
Secondary endpoints 
The short- and long-term adverse effects will 
be determined.  The overall survival rate will 
be calculated.  Patterns of failure analysis will 
be performed.  Health related quality of life 
will be measured. 
SAMPLE SIZE BY TREATMENT GROUP 
Three patients will be enrolled per dose level 
per arm.  The maximum number of patients 


 
 
needed for the phase I study will depend on the 
number of dose levels reached.  If all 4 dose 
levels are reached, the maximum number of 
patients will be 15 per arm.   
 
 
SUMMARY OF SUBJECT ELIGIBILITY 
CRITERIA 
Inclusion Criteria 
 Histopathologically confirmed newly 
diagnosed glioblastoma multiforme.  
Diagnosis must be made by surgical biopsy 
or excision. 
 The tumor must be supratentorial in 
location. 
 The planning target volume (tumor plus 
margin) must measure ≤ 150 cm3 in 
volume. 
 Age ≥18 years. 
 Life expectancy of at least 12 weeks. 
 Patient must have adequate organ function 
to tolerate temozolomide (details in the 
protocol). 
 
Exclusion Criteria 
 Patients who have previously been treated 
with brain irradiation to the region that 
would result in overlap of the radiation 
fields. 
 Tumor foci detected below the tentorium. 
 Multifocal disease or leptomeningeal 
spread. 
 Prior allergic reaction to the study drugs 
involved in this protocol. 
 Inability to have neither an MRI nor a CT 
scan. Patients with pacemaker will be 
allowed to undergo CT instead of MRI. 
 Pediatric patients (age <18), pregnant 
women, and nursing patients will be 
excluded.  
INVESTIGATIONAL PRODUCTS 
DOSAGE AND ADMINISTRATION 
N/A 
CONTROL GROUP 
N/A 
PROCEDURES 
N/A 
STATISTICAL CONSIDERATIONS 
N/A 
 


 
 
 


 
 
SCHEMA 
 
 
 
Phase I: 
 
 
 
 
 
PTV (Planning Target Volume) is defined as the residual T1 post-contrast enhancing 
tumor and/or resection cavity + 0.5 cm margin (see Section 4.3.4). 
 
 
Patient Population:  (See Section 3.0 for Eligibility) 
 
Histopathologically confirmed supratentorial glioblastoma multiforme without previous 
radiation to the same region.    
Registration
Stratification:
Arms:
1: PTV size < 60 cm3
2: PTV size 60-150 cm3
Hypofractionated
radiotherapy with concurrent 
temozolomide
Dose Levels:
1: 25 Gy in 5 fractions
2: 30 Gy in 5 fractions
3: 35 Gy in 5 fractions
4: 40 Gy in 5 fractions


 
 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ANC 
Absolute neutrophil count 
CBC 
Complete blood count 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report/Record form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTV 
Clinical Tumor Volume 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
GBM 
Glioblastoma multiforme 
GI 
Gastrointestinal 
GTV 
Gross Tumor Volume 
Hgb 
Hemoglobin 
HRQOL 
Health Related Quality of Life 
IRB 
Institutional Review Board 
IV 
Intravenous 
LLN 
Lower limit of normal  
MR 
Minor response 
MTD 
Maximum tolerated dose 
OS 
Overall survival  
P 
Progressive diseased 
PFS 
Progression free survival  
PLT 
Platelet 
PR 
Partial response 
PTV 
Planning Target Volume 
QD 
Once daily 
RT 
Radiotherapy 
SAE 
Serious adverse event 
SD 
Stable disease 
SRS 
Stereotactic Radiosurgery 
STEAE 
Serious treatment emergency adverse event 
TMZ 
Temozolomide 
 


 
 
1. OBJECTIVES 
 
1.1.Phase I - Primary Objective 
1.1.1 Determine the maximum tolerated dose (MTD), based on acute CNS toxicity at 
30 days, of hypofractionated radiotherapy given in 5 fractions with temozolomide 
for the treatment of glioblastoma multiforme. 
 
 
 
1.2.Secondary Objectives 
1.2.1. Assess the short- and long-term adverse effects. 
1.2.2. Determine the radiographic response rate.   
1.2.3. Determine the overall survival rate. 
1.2.4. Determine the patterns of tumor failure. 
1.2.5. Assess quality of life during treatment. 
 
2. BACKGROUND 
 
1.1. Glioblastoma Multiforme 
High grade gliomas are the most common primary brain tumor.  Glioblastoma 
multiforme (GBM) is characterized by its highly aggressive nature and poor prognosis.  
The annual incidence of GBM in the U.S. is 12,000 and rising.  Multi-modality therapy 
with surgery, radiation (RT), and chemotherapy is the standard treatment for all patients 
whose performance status allows aggressive treatment.  Even after a gross total resection, 
the local recurrence rate is high.  Post-operative radiotherapy has been shown to increase 
local control and overall survival rates(1, 2).  For elderly patients and patients with poor 
performance status, radiation therapy without chemotherapy provides palliation and 
prolongs survival(3). 
 
1.2. Hypofractionated Radiotherapy 
Standard therapy for GBM includes 6 weeks of daily radiation treatments.  This treatment 
course can pose a substantial hardship for patients and their families, particularly for 
those living distant from a radiation facility.  Despite aggressive multimodality treatment, 
the median survival is only 14 months(4). 
 
Compared to standard fractionation, hypofractionated radiotherapy or stereotactic 
radiosurgery (SRS) delivers higher doses of radiation in fewer treatment sessions (5 
treatments versus 30 for conventionally fractionated RT).  SRS for GBM has several 
potential advantages:  First, SRS drastically reduces the total treatment time thereby 
potentially maximizing the patients’ quality of life.  A five week decrease in treatment 
time represents approximately 10% of the median lifespan of these patients.  Similarly, 
this goal on the use of SRS to shorten the treatment time for an otherwise incurable tumor 


 
 
has been studied and achieved for pancreas cancer(5-7).  A similar shortening of 
treatment time has been investigated in breast cancer, where the standard 33 days of 
therapy have been replaced with a single day(8). Second, by shortening the treatment 
duration, hypofractionation may lead to suppression of tumor cell repopulation and 
improve tumor control.  An in vitro study of glioblastoma cell lines have demonstrated 
repopulation of glioblastoma cells during fractionated radiotherapy, thereby requiring 
higher radiation dose to achieve cell kill(9).  Likewise, longer treatment duration has 
been shown to decrease local control in multiple other tumor types(10).  Third, GBM 
may show improved response to higher radiation doses per fraction.  Hypofractionated 
radiotherapy has been shown to cause improved tumor regression in mouse xenografts 
compared to conventional or hyperfractionated radiotherapy(11).  Moreover, GBM 
tumors carrying a p53 mutation are more resistant to conventionally fractionated 
radiotherapy, and improved cell kill has been demonstrated with hypofractionation(12).  
 
Several groups have employed hypofractionated radiotherapy alone, without 
chemotherapy, for treatment of high grade glioma and have shown hypofractionated RT 
to be well tolerated.  Thomas has shown the regimen of 30 Gy in 5 Gy fractions was 
without acute toxicity(13).  Floyd et al. delivered 50 Gy in 5 Gy fractions over a 2-week 
course.  While 3 of 20 patients in this study underwent surgical re-excision due to 
radiation necrosis, these three patients also enjoyed longer survival (range, 9-23 
months)(14).  Hulshof compared conventional fractionation with hypofractionation using 
66 Gy in 2 Gy (conventional fractionation), 40 Gy in 5 Gy, and 28 Gy in 7 Gy fractions.  
Patients treated with the conventional radiation schedule had similar median survival as 
the 28 Gy in 7 Gy fraction group despite having patients with significantly worse 
prognostic factors in the hypofractionation group(15).  In a prospective trial of patients 
older than 60 years, a shorter course of radiotherapy, using 40 Gy in 15 fractions (2.67 
Gy fractions) over 3 weeks, decreased treatment time and corticosteroid requirement 
without negatively affecting survival when compared to conventional radiotherapy (60 
Gy in 2 Gy fractions over 6 weeks)(16).  
 
A major concern of using high doses per fraction is the potential for neurotoxicity. 
Multiple studies have demonstrated doses ranging from 2.5 to 7 Gy per fraction to be 
well tolerated in patients without prior radiation(13, 17-19).  Hypofractionated 
radiotherapy has also been shown to be safe in patients with prior radiation:  In a study by 
Hudes and colleagues, patients with recurrent or persistent malignant glioma who had 
previously received a median dose of 60 Gy (range, 44 – 72 Gy) of external beam 
radiation were treated with stereotactic radiotherapy to target recurrent or persistent 
tumors in a phase I dose escalation study.  Although there was no tumor response to 24 
Gy in 3 Gy fractions, 79% responded to 30 Gy in 3 Gy or 35 Gy in 3.5 Gy fractions.  
There was no grade ≥3 toxicity, and no patient required a re-resection due to toxicity(20).  
Shepherd et al. reported hypofractionated stereotactic radiotherapy in treatment of 
recurrent glioma using 5 Gy fractions to total doses ranging from 20 to 50 Gy to be well 
tolerated, with 36% having reversible steroid-dependent toxicity and only 6% requiring 
reoperation(21). 
 


 
 
 
1.3. Temozolomide 
Temozolomide is an oral alkylating agent.  The benefit of temozolomide was 
demonstrated in a phase III trial of GBM patients randomized to post-operative involved 
field radiation (60 Gy in 2 Gy fractions) with or without concurrent and adjuvant 
temozolomide.  The addition of temozolomide led to a significant improvement in overall 
survival (14.6 vs. 12.1 months)(4).  The safety of radiation dose escalation up to 60 Gy in 
3 Gy per fraction with concurrent temozolomide has been reported, with clinical 
outcomes similar to that of a conventional fractionation regimen.  Only one patient in this 
study suffered a grade 3-4 nausea and vomiting during the adjuvant temozolomide 
administration(22).  Chen and colleagues recently reported their phase I trial of 
hypofractionated intensity modulated radiotherapy (IMRT) with concurrent TMZ for 
primary treatment of GBM(23).  Patients with a tumor up to 6 cm in size were treated 
with a 5 mm margin with escalating doses of IMRT, safely reaching 60 Gy in 10 
fractions.  Even with this extreme hypofractionation with concurrent chemotherapy, with 
potential tumor volumes up to 180 cm3 (6 cm tumor + 5 mm margin), no maximum 
tolerated dose was reached.  
 
 
A 4-week course of hypofractionated intensity-modulated RT with concurrent and 
adjuvant temozolomide has been shown to be well tolerated, with eighty-three percent of 
the patients completing the combined modality treatment.  Compared to conventionally 
fractionated RT, the hypofractionated course decreased the duration of RT treatment 
down to 4 weeks with comparable median overall survival rates(24). 
 
Hypofractionated RT has been used with concurrent temozolomide in treatment of brain 
metastases and appears to be well tolerated, even when the entire brain is irradiated:  
Kouvaris et al. treated patients with brain metastases from solid tumors with whole brain 
radiation to a dose of 36 Gy in 3 Gy fractions with concurrent and adjuvant 
temozolomide and reported minimal side effects(25).  Similarly, Hofman and colleagues 
showed that whole brain RT (20 Gy in 4 Gy fractions or 30 Gy in 3 Gy fractions) and 
stereotactic radiosurgery (20 Gy in a single fraction) with concurrent temozolomide were 
well tolerated(26). 
 
 
Given the preclinical glioblastoma data demonstrating improved tumor control and 
decreased tumor cell repopulation with hypofractionated RT, a study of SRS in 
conjunction with temozolomide for treatment of GBM is warranted.  The goal of this 
phase I study is to determine the maximum tolerated dose (MTD) of five fraction 
stereotactic radiosurgery with concurrent and adjuvant temozolomide for treatment of 
GBM.   
 
 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
 
Refer to the Participant Eligibility Checklist in Appendix A.  


 
 
 
3.1  
Inclusion Criteria 
 
3.1.1 Histopathologically confirmed newly diagnosed glioblastoma multiforme.  
Diagnosis must be made by surgical biopsy or excision. 
 
3.1.2 The tumor must be supratentorial in location. 
 
3.1.3 The planning target volume (PTV), defined as residual T1 post-contrast 
enhancing tumor and/or resection cavity plus 0.5 cm margin, must measure ≤ 
150 cm3 in volume. This volume will not be known at the initial consultation; 
it will be determined once the final radiation plan is completed.  
 
3.1.4 Age ≥18 years. 
 
3.1.5 Life expectancy of at least 12 weeks. 
 
3.1.6 Patient must have adequate organ function as indicated by the following 
laboratory values: 
 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,800 cells /mm3 
Platelets 
≥100,000 cells /mm3 
Hemoglobin 
≥8 g/dL.  If anemia is present to the extent that the hemoglobin 
is <8 g/dL, then correction by transfusion is indicated before 
entry into the study. 
Renal 
 
BUN 
≤ 30 mg/dL 
Creatinine 
≤ 1.7 
Hepatic 
 
Serum total bilirubin 
≤ 2.0  
AST (SGOT) and ALT (SGPT) 
≤ 3 X ULN   
 
 
 
 
 
 
 
 
 
3.1.8 Ability to understand and the willingness to sign a written informed consent 
document 
 
 
3.2  
Exclusion Criteria 
 
3.2.1 Patients who have previously been treated with brain irradiation to the region 
that would result in overlap of the radiation fields. 


 
 
 
3.2.2 Tumor foci detected below the tentorium. 
 
3.2.3 Multifocal disease or leptomeningeal spread. 
 
3.2.4 Prior allergic reaction to the study drugs involved in this protocol. 
 
3.2.5 Inability to have neither an MRI nor a CT scan. Patients with a pacemaker 
must undergo CT instead of MRI to be eligible. 
 
3.2.6 Pediatric patients (age <18), pregnant women, and nursing patients will be 
excluded.  
 
 
 
3.3       Informed Consent Process 
 
Patients who meet the inclusion and exclusion criteria who are seen in the neuro-
oncology, neurosurgery, or radiation oncology clinic will be identified for 
recruitment.  Patients will be evaluated by a multi-disciplinary team composed of 
radiation oncologists, neurosurgeons, and neuro-oncologists.  During their visit, either 
a physician or a research coordinator will explain the study to the patient.  They will 
be given the informed consent form to read.  If they agree to participate, they will be 
asked to sign the consent form prior to participating. 
 
 
 


 
 
4. TREATMENT PLAN 
 
4.1  
Pretreatment evaluation 
 
Patients will be evaluated by a multi-disciplinary team composed of radiation 
oncologists, neurosurgeons, and neuro-oncologists to assess for their eligibility.  
Patient’s oncologic history, presenting symptoms, physical examination, pathology, 
and imaging studies will be reviewed.  Patients will be evaluated for surgical 
candidacy and respectability.   
 
4.2  
Surgical treatment 
 
Patients who are surgical candidates will undergo a surgical resection prior to 
radiotherapy.  Patients whose tumors are unresectable or are not good surgical 
candidates will undergo a biopsy for tissue diagnosis.  
 
4.3  
Radiation Therapy 
 
1.1.1. Dose specifications/escalation 
Radiation will be delivered in five fractions.  Provided that the MTD has not been 
reached, the total dose will be increased as follows: 
 
Dose Level Dose Per Fraction (Gy) Total Dose (Gy) 
1 
5 
25 
2 
6 
30 
3 
7 
35 
4 
8 
40 
 
There will be 2 arms to this study: 
 
Arm PTV volume (cm3) 
1 
< 60 
2 
60-150 
 
 
A minimum observation period of 30 days following radiotherapy is required prior 
to proceeding with the next higher dose level. 
 
Common Terminology Criteria for Adverse Events (CTCAE) v4.0 will be used to 
grade adverse events: 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html) 
A dose limiting toxicity (DLT) is defined as a treatment related grade 3 - 5 CNS 
toxicity.  Acute toxicity is defined as occurring within <30 days of the end of 


 
 
radiotherapy.  Late toxicity is defined as occurring >30 days of the end of 
radiotherapy. The highest dose achieved with an acceptable level of toxicity will be 
considered the MTD.  The highest dose level allowed in this study is 40 Gy.  The 
occurrence of late toxicities will be continuously monitored.  If a late DLT occurs in 
2 patients at a certain dose level after the radiation dose had already been escalated 
to the next level, the MTD will be backtracked to the level below the one at which 
the DLTs occurred.  
Dose escalation will follow a traditional 3 + 3 design:   
  
Number of 
Patients with DLT 
at a Given Dose 
Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
1 out of 3 
Enter at least 3 more patients at the current dose level. 
 If 0 of these 3 experiences a DLT (i.e., 1 out of 6), then 
proceed to next dose level. 
 If 1 or more of these 6 experiences a DLT (2 or more out of 
6), then dose escalation will be stopped.  Three additional 
patients will be entered at the next lower dose level if only 
3 patients were previously entered. 
>1 out of 3 
Dose escalation will be stopped. Three additional patients will be 
entered at the next lower dose level if only 3 patients were 
previously entered. 
 
Should a patient not be evaluable at 30 days (due to death unrelated to protocol treatment 
or loss to follow-up or discontinuation of the protocol follow-up per patient preference), 
then additional patients may be enrolled on each arm such that at least 3 are evaluable for 
DLT.   
 
1.1.2. Technical factors 
Treatment shall be delivered using the Trilogy™ or TrueBeam Linear Accelerator 
(Varian Medical Systems, Palo Alto, CA) or the CyberKnife™ Robotic 
Radiosurgery System (Accuray, Sunnyvale, CA). 
 
1.1.3. Localization, simulation, and immobilization 
The patient shall be treated in the supine position.  An aquaplast head mask will be 
used to ensure adequate immobilization during therapy.    
 


 
 
1.1.4. Target Definition 
1.1.4.1. 
Gross Tumor Volume (GTV) 
The gross tumor volume (GTV) will be contoured using the post-operative 
contrast-enhanced MRI and is defined depending on the type of resection 
as follows: 
 Gross total resection:  GTV = tumor resection cavity; 
 Partial resection:  GTV = residual enhancing tumor plus resection 
cavity; 
 Biopsy only:  GTV = enhancing tumor only. 
1.1.4.2. 
Clinical Tumor Volume (CTV) 
The clinical tumor volume (CTV) is defined as GTV plus a 0.5 cm 
margin.  This margin may be as small a 0 mm near structures which 
represent an anatomic border for tumor spread (e.g., falx, calvarium, 
tentorium). No attempt will be made to include a T2 or FLAIR signal. 
1.1.4.3. 
Planning Target Volume (PTV) 
The planning target volume (PTV) is the same as the CTV, without 
additional margin. 
1.1.5. Radiation Dosimetry 
1.1.5.1. 
The prescription isodose line shall cover at least 90%, with a goal of at 
least 95% of the PTV, typically with 10-30% heterogeneity (i.e., the 
prescription isodose line shall be at 70-90%).  The PTV coverage may be 
lower than 95% in order to meet the dose constraints of critical structures.  The 
conformity indices should be between 1.0 and 1.75.  
1.1.6. Critical Structures 
Critical normal structures (e.g., optic apparatus, brain stem) will be contoured and 
their doses minimized.  Maximum doses to critical structures are as follows: 
 
1.1.6.1. 
 Optic nerves and optic chiasm: 98% of volume to receive <27.5 Gy in 5 
fractions. This value is radiobiologically equivalent to 47 Gy in 2 Gy fractions. 
 
1.1.6.2. 
Brain Stem: 98% of volume to receive <30 Gy in 5 fractions.  This value 
is radiobiologically equivalent to 54 Gy in 2 Gy fractions. 


 
 
 
1.1.6.3. 
The radiation isodose line coverage of the PTV shall be decreased in order 
to meet these dose limits. 
 
 
4.4  
Drug therapy 
 
1.2.6. Temozolomide  
Temozolomide 
(3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-
carboxamide).  At physiologic pH, temozolomide undergoes spontaneous hydrolysis 
to the active compound MTIC (3-methyl-(triazen-1-yl)imidazole-4-carboxamide).  
MTIC is thought to kill cells by alkylation of DNA. 
 
1.2.7. Dose definition and administration 
Oral temozolomide (75 mg/m2/day) will be administered daily during radiotherapy.  
The first dose of temozolomide will begin the day before the first fraction of 
radiation.  The last dose will be taken the day of the last fraction of radiation.  
Following radiotherapy, maintenance temozolomide will be prescribed at the 
discretion of the treating neuro-oncologist. 
 
1.2.8. How Supplied 
Temozolomide capsules are made in 5 mg, 20 mg, 100 mg, and 250 mg doses. 
 
1.2.9. Known Adverse Events 
  
Concomitant Phase 
Radiotherapy + TEMODAR® 
(n=228)  
Maintenance Phase 
TEMODAR® 
(n=224) 
Adverse event 
Number (%) of patients 
 
  
All 
Grade ≥ 3 
All 
Grade ≥ 3 
 
Alopecia 
199 (69) 
0 
124 (55) 
0 
 
Fatigue 
156 (54) 
19 (7) 
137 (61) 
20 (9) 
 
Nausea 
105 (36) 
2 (1) 
110 (49) 
3 (1) 
 
Vomiting 
57 (20) 
1 (<1) 
66 (29) 
4 (2) 
 
Anorexia 
56 (19) 
2 (1) 
61 (27) 
3 (1) 
 


 
 
Headache 
56 (19) 
5 (2) 
51 (23) 
9 (4) 
 
Constipation 
53 (18) 
3 (1) 
49 (22) 
0 
 
Convulsions 
17 (6) 
10 (3) 
25 (11) 
7 (3) 
 
Thrombocytopenia 
11 (4) 
8 (3) 
19 (8) 
8 (4) 
 
 
1.2.10. Contraindications 
Temozolomide is contraindicated in patients with hypersensitivity to temozolomide, 
any of the capsule components, or DTIC. 
 
 
4.5  
General Concomitant Medication and Supportive Care Guidelines 
 
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.  
 
4.5.1. Steroids may be given as clinically indicated. The total dose must be recorded 
pretreatment and at the time of each treatment evaluation. Steroids will be used in 
the smallest dose that will afford the patient satisfactory neurologic function and the 
best possible quality of life.  
 
4.5.2. Antiemetics: Patients may be given antiemetics prior to each daily dose of 
temozolomide. The antiemetic and dosing will be left to the treating physician’s 
discretion.  Other antiemetics such as 5HT3 antagonists or lorazepam (Ativan®) 
may be used at the discretion of the investigator for late nausea and vomiting.  
 
  
 
4.5.3. Anticoagulants: Patients who are taking warfarin (Coumadin®) may participate in 
this study; however, it is recommended that international normalization ration 
(INR) or prothrombin time be monitored carefully.  The frequency of INR 
determinations is left to the clinical judgment of the investigator. Subcutaneous 
heparin or fractionated heparin products are also permitted.  
 
4.5.4. Pneumocystis prophylaxis: Prophylaxis against Pneumocystis carinii pneumonia is 
typically recommended for all patients receiving concomitant temozolomide and 
radiotherapy for the 42-day regimen.  Since the duration of 
radiotherapy/temozolomide regimen is shorter on this protocol, the use of 
pneumocystis prophylaxis is left to the clinical judgment of the investigator.  All 
patients receiving temozolomide, particularly patients receiving steroids, should be 
observed closed for the development of Pneumocystis pneumonia.  Acceptable 
regimens are:   


 
 
 
4.5.4.1. Trimethoprim-sulfamethoxazole: Trimethoprim will be given at 160 
mg/sulfamethoxazole 800 mg daily for 3 days each week, beginning on day 1 
of radiation therapy and continuing for 14 days after completion or radiation 
therapy.  
 
4.5.4.2. For subjects allergic to sulfa compounds, pentamidine (or dapsone or 
atovaquone) may be the drug used. The choice is left to the discretion of the 
investigator.  
 
4.5.5. Infections are to be treated with the appropriate antibiotics and recorded. 
 
4.5.6. Analgesics and any other medications are to be specified and their doses recorded. 
 
4.5.7. Recall blisters post-sun exposure can be treated with Domeboro soaks. If 
neuropathy occurs, patients may be placed on gabapentin.  
 
4.5.8. No other chemotherapy treatment is permitted during protocol treatment.  
 
4.6  
Duration of Therapy 
 
 
 
The first dose of temozolomide will begin the day before the first fraction of 
radiation.  It will be taken through the day of the last fraction of radiation.  
Following radiotherapy, maintenance temozolomide will be prescribed at the 
discretion of the treating neuro-oncologist. 
 
 
 
 
4.7  
Duration of Follow Up 
 
 
Patient follow-up schedule is summarized under section 8. Study Calendar.   
The following will be obtained at pre-treatment evaluation and at each follow-up time 
points:  Neurologic history and physical examination, KPS, steroid use assessment, 
and toxicity evaluation (see Follow-up assessment form).  MRI with gadolinium will 
be obtained pre-treatment and at 1, 6, and 12 months following treatment until 
progression is documented.   
In addition to the follow-up schedule outlined in section 8, additional clinical follow-
up and MRI scans will be obtained based on clinical progress during the first 12 
months following radiation. 
After the first 12 months or after the documentation of disease progression, patients 
will be followed every 3-6 months at the discretion of the treating physician.   
For those subjects who are unable to come for clinic visits, clinical follow-up 
information will be obtained via 1) a phone call to the patient and/or 2) clinic source 
document from his/her local physician.  For patients unable to return to for imaging 
studies, source documents from outside institutions will be used to document imaging 
follow-up. 


 
 
 
 
4.8 
Criteria for Removal from Study 
 
 Disease progression or death 
 Intercurrent illness that prevents further administration of treatment:  a 
condition, injury, or disease unrelated to cancer, that renders continuing 
temozolomide or radiation treatment unsafe or regular study visits impossible, 
including, but not limited to, active infection, symptomatic congestive heart 
failure, unstable angina pectoris, cardiac arrhythmia, pregnancy, or psychiatric 
illness that would limit compliance with study requirements.  
 Unacceptable adverse event(s) (see adverse events) 
 Patient decides to withdraw from the study 
 General or specific changes in the patient’s condition that render the patient 
ineligible for the study 
 Non-compliance with study medication or protocol-required evaluations and 
study visits 
 Inability of subject to comply with study requirements 
 Determination by the investigator that it is no longer safe for the subject to 
continue therapy 
 Patients who inadvertently become pregnant  
 At the discretion of the treating investigators 
 
Subjects/patients may withdraw at any time or be dropped from the study at the 
discretion of the investigator should any untoward effects occur. In addition, a 
subject/patient may be withdrawn by the investigator if he/she violates the study plan 
or for administrative and/or other safety reasons.  Any adverse experiences which are 
present at the time of discontinuation/withdrawal should be followed until resolution 
or stabilization. 
Subjects who are discontinued from the study will still be followed for disease 
progression and survival. 
 
If the reason for withdrawal from the trial is the death of the subject, the two options 
for categorizing withdrawal are either progressive disease or an adverse event (AE; 
more than one AE may be documented as a reason for withdrawal).  Only one event 
will be captured as the cause of death.  Note that death is an outcome and not an AE.  
 
All trial treatment-related toxicities and SAEs must be followed up until resolution. 
 
Subjects/patients who discontinue from the study for reasons unrelated to the study 
(e.g., personal reasons, or adverse events after registration but prior to receiving study 
therapy) may be replaced as required for the study to meet its objectives.  The 
decision to remove a subject/patient and to replace dropouts will be made by the 
treating investigator.  The replacement will generally receive the same treatment or 


 
 
treatment sequence (as appropriate) as the allocation number replaced. 
 
4.9 
 Alternatives 
 
Alternative 
treatments 
include 
conventionally 
fractionated 
external 
beam 
radiotherapy with or without temozolomide or no therapy. 
 
 
 
 
 
 
 
4.10 
 Compensation 
 
Subjects will not be paid for their participation in the study.  
 
 
 
5. DOSING DELAYS/DOSE MODIFICATIONS 
 
Not applicable due to the short treatment duration of this study. 
 
 
6. ADVERSE EVENTS AND REPORTING PROCEDURES 
 
6.1 Potential Adverse Events 
 
6.1.1. Radiation 
 
6.1.1.1.Early, < 30 days from treatment:  Expected adverse events include fatigue, 
alopecia, skin erythema, serous otitis, radiation pharyngitis, headache, neck 
pain, nausea and vomiting, and lethargy.   
6.1.1.2. 
Late, > 30 days from treatment:  Possible adverse events include focal 
neurologic deficits, memory difficulties, dementia, radiation necrosis, and 
radiation induced neoplasms.   
6.1.2. Temozolomide 
 
During the concomitant phase (temozolomide (TMZ) + radiotherapy) of the 
Stupp’s trial(4), adverse reactions including thrombocytopenia, nausea, vomiting, 
anorexia, and constipation were more frequent in the TMZ + RT arm. The 
incidence of other adverse reactions was comparable between the arms with and 
without temozolomide. The most common adverse reactions across the 
cumulative TMZ experience were alopecia, nausea, vomiting, anorexia, headache, 
and constipation.  Forty-nine percent (49%) of patients treated with TMZ reported 
one or more severe or life-threatening reactions, most commonly fatigue (13%), 
convulsions (6%), headache (5%), and thrombocytopenia (5%).   
 
Number (%) of patients with adverse reactions: 
  
 
RT Alone  
TMZ + conventional 
Maintenance phase 


 
 
n=285 
RT; n=288 
TMZ; n=224 
 
All 
Grade 3 
All 
Grade 3 
All 
Grade 3 
General 
 
 
 
 
 
 
Anorexia 
25 (9) 
1 (<1) 
56 (19) 
2 (1) 
61 (27) 
3 (1) 
Dizziness 
10 (4) 
0 
12 (4) 
2 (1) 
12 (5)  
0 
Fatigue 
139 (49) 
15 (5) 
156 (54) 
19 (7) 
137 (61) 
20 (9) 
Headache 
49 (17) 
11 (4) 
56 (19) 
5 (2) 
51 (23) 
9 (4) 
Weakness 
9 (3) 
3 (1) 
10 (3) 
5 (2) 
16 (7) 
4 (2) 
Central Nervous 
System 
 
 
 
 
 
 
Confusion 
12 (4) 
6 (2) 
11 (4) 
4 (1) 
12 (5) 
4 (2) 
Convulsions 
20 (7) 
9 (3) 
17 (6) 
10 (3) 
25 (11) 
7(3) 
Memory 
Impairment 
12 (4) 
1 (<1) 
8 (3) 
1 (<1) 
16 (7) 
2 (1) 
Eye 
 
 
 
 
 
 
Vision Blurred 
25 (9) 
4 (1) 
26 (9) 
2 (1) 
17 (8) 
0 
Immune 
 
 
 
 
 
 
Allergic Reaction 
7 (2) 
1 (<1) 
13 (5) 
0 
6 (3) 
0 
Gastrointestinal 
 
 
 
 
 
 
Abdominal pain 
2 (1) 
0 
7 (2) 
1 (<1) 
11 (5) 
1 (<1) 
Constipation 
18 (6) 
0 
53 (18) 
3 (1) 
49 (22) 
0 
Diarrhea 
9 (3) 
0 
18 (6) 
0 
23 (10) 
2 (1) 
Nausea 
45 (16) 
1 (<1) 
105 (36) 
2 (1) 
110 (49) 
3 (1) 
Stomatitis 
14 (5) 
1 (<1) 
19 (7) 
0 
20 (9) 
3 (1) 
Vomiting 
16 (6) 
1 (<1) 
57 (20) 
1 (<1) 
66 (29) 
4 (2) 
Injury 
 
 
 
 
 
 
Radiation injury 
NOS 
11 (4) 
1 (<1) 
20 (7) 
0 
5 (2) 
0 
Musculoskeletal 
 
 
 
 
 
 
Arthralgia 
2 (1) 
0 
7 (2) 
1 (<1) 
14 (6) 
0 
Platelet 
 
 
 
 
 
 
Thrombocytopenia 
3 (1) 
0 
11 (4) 
8 (3) 
19 (8) 
8 (4) 
Psychiatric 
 
 
 
 
 
 
Insomnia 
9 (3) 
1 (<1) 
14 (5) 
0 
9 (4) 
0 
Respiratory 
 
 
 
 
 
 
Coughing 
3 (1) 
0 
15 (5) 
2 (1) 
19 (8) 
1 (<1) 
Dyspnea 
9 (3) 
4 (1) 
11 (4) 
5 (2) 
12 (5) 
1 (<1) 
Skin 
 
 
 
 
 
 
Alopecia 
179 (63) 
0 
199 (69) 
0 
124 (55) 
0 
Dry skin 
6 (2) 
0 
7 (2) 
0 
11 (5) 
1 (<1) 
Erythema 
15 (5) 
0 
14 (5) 
0 
2 (1) 
0 
Pruritus 
4 (1) 
0 
11 (4) 
0 
11 (5) 
0 
Rash 
42 (15) 
0 
56 (19) 
3 (1) 
29 (13) 
3 (1) 


 
 
Other 
 
 
 
 
 
 
Taste perversion 
6 (2) 
0 
18 (6) 
0 
11 (5) 
0 
 
6.1. Adverse Event Reporting 
 
The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
used for grading of all adverse events.    
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html) 
An adverse event is defined as any unfavorable and unintended change in the structure 
or function of the body temporally associated with the treatment.  Any worsening (i.e., 
any clinically significant adverse change in frequency and/or intensity) of a preexisting 
condition which is temporally associated with treatment, is also an adverse experience. 
In the event of an adverse event the first concern will be for the safety of the subject.  All 
subjects/patients with serious adverse experiences must be followed up for outcome. 
 
Serious Adverse Experiences are: 
Any untoward medical occurrences that at any dose: 
 Results in death, 
 Is life-threatening, 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 
 Results in persistent or significant disability/incapacity 
 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious.  
 
If disease progression is noted during a protocol-specified reevaluation of the status of a 
patient’s cancer, and the progression is manifested solely by result of radiologic imaging, 
that occurrence of progressive disease will NOT be recorded as an adverse experience.   
Each occurrence of a given adverse event will be recorded. Only the most severe grade 
over the course of a given episode will be recorded. 
Serious adverse events occurring after a patient is discontinued from the study will NOT 
be reported unless the investigator feels that the event may have been caused by a 
protocol procedure.  Study-specific clinical outcomes of death because of disease 
progression are exempt from serious adverse event reporting, unless the investigator 
deems them related to a protocol procedure.   
 
In general, serious adverse events assessed as clearly being due to disease progression 
and not due to a protocol procedure should be excluded from adverse event reporting. 


 
 
However, in cases where the specificity or severity of an event is not consistent with the 
risk information, the event should be reported. 
 
All STEAEs will be recorded on Adverse Events Communication Form and reported to: 
 
 
 
1) Study Coordination Center/Principal Investigator 
 
Stanford University/ Dr. Scott Soltys 
       
 
2) Stanford University Cancer Clinical Trials Office (Study Coordination Center) 
 
Stanford University Cancer Center 
 
Administrative Panels Office 
 
Stanford University, Stanford, CA  94305-5548 
 
 
 
 
 
 
RETENTION OF RECORDS 
 
All documentation of adverse events and all IRB correspondence will be retained for at 
least 2 years after the investigation is completed. 
 
 
7. CORRELATIVE/SPECIAL STUDIES 
 
N/A 
 
 
8. STUDY CALENDAR 
 
Parameters 
Pre-Entry 
1  
montha 
6 monthe 
12 monthe 
History/ 
Physical 
Exam 
X 
X 
X 
X 
KPS 
X 
X 
X 
X 
HRQOLb 
X 
X 
X 
X 
Labsc 
X 
 
 
 
Brain MRI or 
CTd 
X 
X 
X 
X 
Steroid use 
Assessment 
X 
X 
X 
X 
Toxicity 
Evaluation 
 
X 
X 
X 
 
a ± 7 days 


 
 
b EORTC-QLQ C30 and BN-20, MDASI-BT 
c Laboratory tests: complete blood count, general chemistry panel, and 
comprehensive metabolic panel 
dMRI schedule may change as indicated should patient have clinical 
deterioration; CT instead of MRI is acceptable if patient has pacemaker. 
e ± 1 month 
 
 
9. MEASUREMENT OF EFFECT 
 
9.1 Anti-tumor Effect 
 
Brain MRI will be obtained at 1st, 6th, and 12th months following radiotherapy until 
disease progression.  Patients may require imaging prior to the study defined 
assessment points should clinical deterioration warrant; should this occur, effort will 
be made to return to the protocol defined imaging schedule.  However, clinical 
evaluation by the treating physicians may warrant an altered schedule. After the first 
year or after the documentation of disease progression, brain MRI will be obtained 
every 3-6 months at the discretion of the treating physician.   
 
For patients unable to return to for imaging studies, source documents from outside 
institutions will be used to document imaging follow-up. 
 
9.1.2 Disease Parameters 
 
Local tumor progression is defined as the radiographic appearance of a new or 
increasing enhancing lesion within the radiosurgical target volume.  Patients with 
increased tumor size on MRI may continue on the protocol until true tumor 
progression (i.e., not pseudo-progression) is determined by the treating 
physicians. 
 
9.1.3 Methods for Evaluation of Measurable Disease 
 
9.1.4 Response Criteria 
 
 
The primary measure of response will be by serial measures of the 
product of the two largest cross-sectional diameters. Response will also be 
evaluated in this study using the following criteria: 
 
9.1.4.1 Complete response (CR): Circumstance when the enhancing tumor 
is no longer seen by neuroimaging. 
9.1.4.2 Partial response (PR):  Decrease of >50% in the product of the two 
greatest diameters on the follow-up MRI scan.  No new lesions 
may appear.  The dose of dexamethasone must be the same or 
lower than at baseline. 


 
 
9.1.4.3 Minor response (MR): Decrease of <50% in the product of the two 
greatest diameters on the follow-up MRI scan.  Neither partial 
response or progressive disease. 
9.1.4.4 Progression (P):  A >25% increase in tumor area (product of the 
two greatest diameters) provided that the patient has not has a 
decrease in steroid dose since the last evaluation period.  A 
concomitant decrease in steroid dose will rule out a progression 
designation during the first 2 months after the completion of XRT. 
 
 
9.2 Other Response Parameters 
 
9.2.1 Acute and late side effects will be assessed. 
Common Terminology Criteria for Adverse Events (CTCAE) v4.0 will be used 
to grade adverse events.  Acute toxicity is defined as occurring within 30 days 
of radiotherapy.  Late toxicity is defined as occurring more than 30 days 
following the radiotherapy treatment.  
 
9.2.2 The progression-free survival rate will be determined. 
9.2.3 The overall survival rate will be determined. 
9.2.4 The patterns of tumor recurrence will be determined. 
9.2.5 The Health Related Quality of Life (HRQOL) will be measured used the validated 
EORTC QLQ-C30 general and BN-20 brain tumor specific scales as well as the 
M.D. Anderson Symptom Inventory –Brain Tumor (MDASI-BT)   
For those subjects unable to appear in person for clinic visits, HRQOL 
questionnaires will be completed via a telephone interview or mail. 
 
10. 
DATA REPORTING / REGULATORY CONSIDERATIONS 
 
10.1 Monitoring plan 
 
Stanford Cancer Center (SCC) Data and Safety Monitoring Committee (DSMC) will 
be responsible for monitoring the research yearly and will operate independently from 
the clinical investigators. The primary responsibility of the DSMC is to review the 
reported study data to confirm it is accurate, complete, and verifiable from source 
documents.  The DSMC will also confirm that the conduct of the trial maintains the 
safety and well being of human subjects, and is in compliance with the currently 
approved protocol, with GCP, and with applicable regulatory requirements.  Study 


 
 
safety data will be reviewed by the DSMC in the form of summary reports or data 
listings on a regular basis. 
 
10.2  Stopping rules (for the individual patient and for the study as a whole) 
 
Dose escalation will follow a traditional 3 + 3 design.   
 
Number of 
Patients with DLT 
at a Given Dose 
Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
1 out of 3 
Enter at least 3 more patients at the current dose level. 
 If 0 of these 3 experiences a DLT (i.e., 1 out of 6), then 
proceed to next dose level. 
 If 1 or more of these 6 experiences a DLT (2 or more out of 
6), then dose escalation will be stopped.  Three additional 
patients will be entered at the next lower dose level if only 
3 patients were previously entered. 
>1 out of 3 
Dose escalation will be stopped. Three additional patients will be 
entered at the next lower dose level if only 3 patients were 
previously entered. 
 
Should a patient not be evaluable at 30 days (due to death unrelated to protocol treatment 
or loss to follow-up or discontinuation of the protocol follow-up per patient preference), 
then additional patients may be enrolled on each arm such that at least 3 are evaluable for 
DLT.   
The occurrence of late toxicities will be continuously monitored. If a late DLT occurs in 
2 patients at a certain dose level after the radiation dose had already been escalated to the 
next level, the MTD will be backtracked to the level below the one at which the DLTs 
occurred. 
 
 
10.3 Confidentiality  
 
All signed informed consents and data files (contains patients’ names, medical 
record numbers, treatment, and follow-up information) for this study will be kept in 
a secure office in the department of Neurosurgery and Radiation Oncology.  The 
electronic data file for this study, which contains patients’ names, medical record 
numbers, treatment, and follow-up information, is kept under password protection. 
 
11. STATISTICAL CONSIDERATIONS 


 
 
 
11.1Endpoints 
 
11.1.1 Phase I Primary endpoint 
 
The MTD and DLT of hypofractionated radiotherapy with temozolomide will be 
determined. 
 
 
11.1.2 Secondary endpoints 
 
The short- and long-term adverse effects will be determined.  The overall survival 
rate will be calculated. Radiographic response rates and patterns of local tumor 
recurrence will be determined. Health related quality of life will be assessed. 
 
11.2Sample Size 
 
11.2.1 Accrual estimates 
 
Three patients minimum enrolled per dose level, plus 3 additional at the dose 
level of the MTD.  The maximum number of patients needed for the phase I study 
will depend on the number of dose levels reached.  If all four dose levels are 
reached, the maximum number of patients will be 15 per arm.   
 
 
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APPENDICIES  
 
A. Participant Eligibility Checklist  
 
I. Protocol Information: 
 
Protocol Title: 
A Phase I/II Trial of Temozolomide and Hypofractionated 
Radiotherapy in Treatment of Supratentorial Glioblastoma 
Multiforme 
Protocol Number: 
17774 
Principal Investigator: 
Scott Soltys, MD 
 
II. Subject Information: 
 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
 
III. Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
Article I. 
Supporting 
Documentation* 
1. Histopathologically confirmed 
newly diagnosed glioblastoma 
multiforme.  Diagnosis must be 
made by surgical biopsy or excision. 
 
 
      
2. Is the tumor must be supratentorial 
in location? 
 
 
      
3. Does the planning target volume 
(PTV), defined as residual T1 post-
contrast enhancing tumor and/or 
resection cavity plus 0.5 cm margin, 
measure ≤ 150 cm3 in volume? 
 
 
      
4. Is the patient age 18 years or 
greater? 
 
 
      
5. Does the patient have a life 
expectancy of at least 12 weeks? 
 
 
      
6. Does the patient have adequate 
organ function? Laboratory values 
are documented below: 
 
 
      
 
Laboratory Test 
(Date of test: __________) 
Test is within 
protocol guideline 
(Check box if 
Patient Value:  
Protocol Guideline: 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*
A
ll subject files must include supporting documentation to confirm subject eligibility. 
The method of confirmation can include, but is not limited to, laboratory test results, 
radiology test results, subject self-report, and medical record review. 
 
IV.  Statement of Eligibility 
– From CBC 
YES) 
Absolute neutrophil count (ANC) 
 
 
≥1,800 cells /mm3 
Platelets 
 
 
≥100,000 cells /mm3 
Hemoglobin 
 
 
≥8 g/dL 
Renal 
– From Basic or Comprehensive 
Metabolic Panel 
 
 
 
BUN 
 
 
≤ 30 mg/dL 
Creatinine 
 
 
≤ 1.7 
Hepatic   
– From Comprehensive Metabolic 
Panel 
 
 
 
Serum total bilirubin 
 
 
≤ 2.0  
AST (SGOT) and ALT (SGPT) 
 
 
≤ 3 X ULN   
Exclusion Criteria 
(From IRB approved protocol) 
 
1. Has the patient been previously 
treated with brain irradiation to 
the region that would result in 
overlap of the radiation fields? 
 
 
      
2. Are tumor foci detected below 
the tentorium? 
 
 
      
3. Is there multifocal disease or 
leptomeningeal spread? 
 
 
      
4. Is there any documentation of 
prior allergic reaction to the 
study drugs involved in this 
protocol? 
 
 
      
5. Is the patient unable to undergo 
an MRI OR CT scan? 
 
 
      
6. Is the patient under age 18, 
pregnant, or nursing? 
 
 
      


 
 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study. This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.   
 
 
 
Treating Physician Signature: 
Date: 
Printed Name: 
 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
 
Study Coordinator Signature: 
Date: 
Printed Name: 
 
 
 
 
 


 
 
B. Participant Initial Evaluation and Follow-Up Forms: 
 
Protocol ID: Hypofractionated Radiotherapy for Treatment of GBM 
Patient Initial Consult Form 
 
Date of visit:  ______________________ 
Study Arm:   #1: PTV <60mL 
 #2: PTV 60-150mL 
 
 
 
 Pt deemed ineligible based on final PTV volume of: _________mL  
Dose Level:  25Gy 
30Gy 
35Gy 
40Gy 
 
 
Patient Number at this Dose Level: _____________ 
 
Done If done: 
Not Done 
History/Physical 
Exam 
 
Date of H/P:  _______________ 
 
KPS Assessment 
 
KPS:  ______ 
 
QOL Forms: 
EORTC QLQ-C30 + 
BN-20 
MDASI-BT 
 
Date: _____________ 
 
Decadron 
 
 No/ Yes; Dose ________________ 
 
Brain MRI 
Date:  _____________ 
 
Protocol Lesion Size (from treatment plan):  
Volume ____________________mL 
Measurement (2 greatest cross sectional diameters): 
           ________ mm   x  ________ mm = _________ 
Final PTV size:  ___________mL 
 


 
 
Protocol ID: Hypofractionated Radiotherapy for Treatment of GBM 
Patient Follow-up Form 
 
Date of follow-up visit:  _________________ 
 Treatment Date: 
_____________________ 
Study Arm:   #1: PTV <60mL 
 #2: PTV 60-150mL 
  
Dose Level:  25Gy 
30Gy 
35Gy 
40Gy 
 
 
Patient Number on this Dose Level: _____________ 
Follow-up time: 
   1 month;   
  6 months;                      
 12 months;   Other:  
____________________ 
 
 
Done If done: 
Not Done 
KPS Assessment 
 
KPS:  ______ 
 
QOL Forms: 
EORTC QLQ-C30 + 
BN-20 
MDASI-BT 
 
Date: _____________ 
 
Decadron 
 
 No         Yes; Dose ________________ 
 
Brain MRI 
Date:  _____________ 
 
Protocol Lesion Size (from current MRI):  
Measurement (2 greatest cross sectional diameters): 
             ________ mm   x  ________ mm = 
_________ 
Assessment (see below): 
      Complete Response    Partial Response 
      Minor Response          Progression 
 
Toxicity Evaluation 
 
NONE 
Toxicity Present (Grade per CTCAE): 
 
 
 
CNS Toxicity is related to Protocol Treatment: 
         Not applicable     Yes      No 
 
 
Comments / Notes: 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date of next follow-up visit:  ______________________ 
Orders for next follow-up visit: 
 
 
 
 
MRI 
Assessment: 
Complete response (CR): Circumstance when the enhancing tumor is no longer seen by neuroimaging. 
Partial response (PR):  Decrease of >50% in the product of the two greatest diameters on the follow-up MRI 
scan.  No new lesions may appear.  The dose of dexamethasone must be the same or lower than at baseline. 
Minor response (MR): Decrease of <50% in the product of the two greatest diameters on the follow-up MRI 
scan.  Neither partial response or progressive disease. 
Progression (P):  A >25% increase in tumor area (product of the two greatest diameters) provided that the 
patient has not has a decrease in steroid dose since the last evaluation period.  A concomitant decrease in steroid 
dose will rule out a progression designation during the first 2 months after the completion of XRT. 
 
1 month F/U 
6 month F/U 
12 month F/U 
Other 
MRI @ 1 mo 
MRI @ 6 mo 
MRI @ 12 
month