Clinical trial NCT01478854
Conditions: Glioblastoma Multiforme
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2011-12-27; Completion date: 2018-04-25
Enrollment: 33 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The long term goal of this research is to establish whether NPC sparing RT techniques improve neurocognitive outcomes compared to conventional RT for brain tumors. If the proposed study demonstrates that NPC sparing RT is not associated with increased LR in the spared regions of the brain compared to conventional RT, it will ideally serve as the foundation for a future multi-institutional randomized controlled trial comparing neurocognitive outcomes in patients treated with NPC-sparing RT versus conventional radiation therapy.

Detailed description:
Radiation therapy (RT) is an integral component of the management of brain tumors, but cognitive deficits following cranial irradiation are well documented. There is an association between damage to neural progenitor cells (NPC) and neurocognitive dysfunction. NPC are similarly known to play an important role in recovery from damage to the brain, including radiation-induced damage. However NPC are extremely sensitive to radiation. In spite of this information, current RT planning techniques do not limit the radiation dose to the NPC containing regions. Recent human studies have demonstrated that it is possible to use intensity modulated radiation therapy to reduce the radiation dose to NPC containing regions during RT for brain tumors, without compromising coverage of the tumor. We hypothesize that NPC-sparing RT will reduce neurocognitive decline following treatment for brain tumors, without compromising tumor local control. However, there is conflicting data regarding the role of NPC in the development of glioblastoma multiforme (GBM). Some studies suggest that GBM are derived from NPC whereas others have associated NPC with improved tumor control following therapy for GBM. Prior to evaluation of neurocognitive outcomes with NPC-sparing RT, it is therefore imperative to evaluate whether NPC-sparing RT techniques lead to increased LR in the spared NPC containing niches of the brain.

The proposed study is designed to evaluate LR in the spared regions of the brain following NPC sparing RT in patients with newly diagnosed GBM. Our research will consist of 3 specific aims: 1) Determine the LR rate at 1 year in the spared NPC containing niches in patients treated with NPC sparing RT for GBM; 2) Quantify the extent of radiation dose sparing to the NPC containing regions that is possible without compromising tumor coverage in patients with GBM; 3) Determine if it is feasible to evaluate cognitive function prospectively in patients undergoing NPC sparing RT for GBM.

The long term goal of this research is to establish whether NPC sparing RT techniques improve neurocognitive outcomes compared to conventional RT for brain tumors. If the proposed study demonstrates that NPC sparing RT is not associated with increased LR in the spared regions of the brain compared to conventional RT, it will ideally serve as the foundation for a future multi-institutional randomized controlled trial comparing neurocognitive outcomes in patients treated with NPC-sparing RT versus conventional radiation therapy.

Arms: arm 1: All subjects are treated with neural progenitor cell sparing radiation to 60 Gy in 2 Gy per day, 30 fractions Concurrent and adjuvant temozolomide chemotherapy
Interventions: intervention 1: Radiation intervention 2: Chemotherapy
Intervention descriptions: intervention 1: Patients will be treated to a total dose of 60 Gy with a once daily fractionation schedule of 2 Gy per fraction, administered five days per week. All patients will undergo CT simulation with intravenous contrast. In addition they will undergo MRI simulation with both T1 with gadolinium as well as FLAIR sequences. They will be treated in a supine position using an aquaplast mask system for immobilization. CT image data will be reconstructed in approximately 3 mm slice thickness and manually coregistered with T1 post-gadolinium and FLAIR sequence MRI. intervention 2: Temozolomide

Protocol documents:
Prot_SAP_000.pdf: 
Version: April 1st, 2014 
TITLE:  A Prospective Trial of Neural Progenitor Cell Sparing Radiation Therapy Plus 
Temozolomide for Newly Diagnosed Glioblastoma Multiforme 
Research Site: 
The Johns Hopkins University School of Medicine 
Principal Investigator: 
Kristin J. Redmond, M.D., M.P.H. 
Department of Radiation Oncology 
401 North Broadway, Suite 1440 
Baltimore, MD 21231 
Telephone: 410-614-1642 
Fax: 410-502-1419 
Email: kjanson3@jhmi.edu 
Co-Investigators: 
Lawrence Kleinberg, M.D., Department of Radiation Oncology 
Stuart Grossman, M.D., Department of Medical Oncology 
Mark Mahone, Ph.D., Department of Neuropsychology 
Claire Ferrigno, N.P., Department of Oncology 
Jaishri Blakeley, M.D., Department of Oncology 
Matthias Holdhoff, M.D., Ph.D., Department of Oncology 
Alfredo Quinones, M.D., Department of Neurosurgery 
John Laterra, M.D., Department of Neurology 
Tracy D. Vannorsdall, Ph.D., Department of Psychiatry 
Statistician: 
Xiaobu Ye, M.D., M.S. 
Telephone: 410-614-6261 
Email: xye3@jhmi.edu 
Study Coordinators: 
Katharine Oteiza
Assadi, Ryan 
Helen Kim, B.S.              
410-614-3158  
              410-955-8652    
  410-614-3950  
 
koteiza1@jhmi.edu             
rassadi1@jhmi.edu 
hkim91@jhmi.edu 
Research Nurses: 
Kelly Szajna, R.N., B.S.N.           Shirl DiPasquale, R.N., 
Beth Griffith, R.N. 
410-502-9242
             410-614-1598 
410-502-9243 
kszajna1@jhmi.edu  
      sdipasq1@jhmi.edu 
 
bgriffit@jhmi.edu  
NCT01478854


 
 
 
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SCHEMA 
 
Patient Eligibility: (See Section 3) 
Newly diagnosed, histologically confirmed glioblastoma multiforme. 
Radiation and medical oncologist recommends adjuvant radiation plus temozolomide. 
Must begin therapy within 12 weeks of biopsy or surgery. 
No prior brain radiation.  
 
 
 
Age ≥ 18 years. 
KPS > 60%.  
 
Signed informed consent. 
 
Treatment Plan: (See Section 5) 
 
 
Eligibility 
 
 
 
 
 
 
 
 
 
 
 
Simulation and treatment planning 
Baseline neuro-cognitive testing 
 
 
 
 
 
Neural progenitor cell sparing radiation to 60 Gy in 2 Gy per day, 30 fractions 
Concurrent and adjuvant temozolomide chemotherapy 
 
 
 
 
 
Follow-up imaging and neurocognitive testing (see section 6) 
 
 
 
   
 
 
Required sample size: 30 patients 
Anticipated accrual: 4-5 patients per month 
 
 


 
 
 
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TABLE OF CONTENTS 
 
 
Page 
SCHEMA ....................................................................................................................................... ii 
 
1. OBJECTIVES ..........................................................................................................................1 
1.1 
Primary Objectives ......................................................................................................1 
1.2 
Secondary Objectives ..................................................................................................1 
 
2. BACKGROUND ......................................................................................................................1 
2.1 
Study Disease and Rationale .......................................................................................1 
2.2 
Temozolomide ..............................................................................................................3 
2.3 
Correlative Studies Background ................................................................................3 
 
3. PATIENT SELECTION..........................................................................................................5 
3.1 
Eligibility Criteria  ......................................................................................................5 
3.2 
Exclusion Criteria ........................................................................................................6 
3.3 
Inclusion of Women and Minorities ..........................................................................6 
 
4. REGISTRATION PROCEDURES ........................................................................................6 
 
5. TREATMENT PLAN ..............................................................................................................7 
5.1 
Surgery and Chemotherapy .......................................................................................7 
5.2       Radiation .......................................................................................................................7 
5.3 
Duration of Follow Up .................................................................................................9 
5.4 
Criteria for Removal from Study ...............................................................................9 
 
6. STUDY CALENDAR ............................................................................................................10 
 
7. MANAGEMENT OF TOXICITY ........................................................................................11 
7.1  
Acute Toxicity.............................................................................................................11 
7.2  
Late Toxicity ...............................................................................................................13 
 
8. STATISTICAL CONSIDERATIONS .................................................................................14 
8.1 
Study Design/Endpoints ............................................................................................14 
8.2 
Sample Size/Accrual Rate .........................................................................................15 
8.3 
Stratification Factors .................................................................................................15 
8.4 
Statistical Methods of Analysis .................................................................................15 
8.5 
Interim Disease Progression Monitoring .................................................................16 
 
9. ADVERSE EVENTS AND REPORTING ...........................................................................17 
9.1 
Definition of Adverse Event ......................................................................................17 
9.2 
Radiation Related Adverse Event.............................................................................17 
9.3 
Chemotherapy Related Adverse Event ....................................................................18 
 
 
 


 
 
 
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10. SERIOUS ADVERSE EVENTS AND REPORTING ........................................................19 
10.1 
Serious Adverse Event ...............................................................................................19 
10.2 
SAE Reporting Guidelines for Johns Hopkins Hospital ........................................19 
 
11. DATA AND SAFETY REPORTING/ REGULATORY CONSIDERATIONS ..............20 
11.1 
Data Quality Monitoring ..........................................................................................20 
11.2 
Data Safety Monitoring .............................................................................................20 
11.3 
Data Reporting ...........................................................................................................20 
11.4 
CTEP Multicenter Guidelines ..................................................................................21 
11.5 
Cooperative Research and Development Agreement (CRADA)/ 
 
Clinical Trials Agreement (CTA) .............................................................................21 
 
REFERENCES .............................................................................................................................22 
 
APPENDIX A 
Performance Status ............................................................................................................25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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1. OBJECTIVES 
 
1.1. 
Primary Objectives  
To estimate the local recurrence (LR) rate at 1 year in the spared neural progenitor 
cell (NPC) containing niches of the brain in patients treated with NPC sparing 
radiation therapy (RT) plus temozolomide for newly diagnosed glioblastoma 
multiforme (GBM). 
 
1.2. 
Secondary Objectives 
 
 
1.2.1 To quantify the extent of radiation dose sparing to the NPC containing regions 
that is possible without compromising tumor coverage in patients with newly 
diagnosed GBM 
 
1.2.2 To examine the relationship between radiation dose to the NPC-containing 
niches and the proximity of the planning tumor volume to the NPC-containing   
regions. 
 
1.2.3  To assess feasibility of evaluating cognitive function prospectively in  
patients undergoing NPC sparing RT for newly diagnosed GBM. 
  
1.2.3 To explore if the potential change from baseline to six months in 
neurocognitive function as measured by the Mini Mental State Exam, Trail 
Making Test, Controlled Oral Word Association test (COWAT), Hopkins 
Verbal Learning Test-Revised, Digit Symbol Substitution Test is related to 
radiation dose to the NPC containing regions in patients treated with NPC 
sparing radiation for newly diagnosed GBM. 
 
2. BACKGROUND 
 
2.1      Study Disease and Rationale 
 
The current standard of care in treatment of newly diagnosed GBM is based on the 
European Organization for Research and Treatment of Cancer and the National Cancer 
Institute of Canada Clinical Trials Group (EORTC/NCIC) phase III clinical trial (1).  
This study randomized patients to surgical resection followed by radiation therapy plus or 
minus concurrent and adjuvant temozolomide and demonstrated an improvement in 
median survival from 12.1 months with standard radiation therapy to 14.6 months with 
the addition of temozolomide.  This marked a significant improvement in 2 year overall 
survival from 10% to 27% with an improvement in five year overall survival from 1.9% 
to 9.8% (2), representing the first report of long term survivals of GBM. 
 
As long term survival from GBM improves, minimizing long term toxicities of therapy 
becomes increasingly important.  Animal studies have shown that new neurons and glia 
are produced throughout adult life from neural stem cell precursors in the subventricular 
zone of the lateral ventricles and the subgranular zone of the hippocampal dentate gyrus 
(3-5).  These cells play an important role in injury repair within the central nervous 


 
 
 
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system (6,7).  Similarly, these cells migrate to the site of inflammation caused by 
irradiation or brain injury (7). 
 
Multiple animal studies have shown that neural progenitor cells are extremely sensitive to 
radiation (8-11).  Tada et al. showed that 2 Gy of radiation effectively killed proliferating 
cells in both the SVZ of the lateral ventricles (8) and the subgranular zone of the dentate 
gyrus (9). The anti-proliferative effects last for up to 15 months after a single radiation 
treatment (12) and are dose dependent (8,9).  
 
There is an association between radiation-induced neural progenitor cell impairment and 
neurocognitive decline after central nervous system irradiation in rodents.  Cranial 
irradiation significantly decreases hippocampal neurogenesis and is associated with 
impaired performance of hippocampal-dependent tasks (13-16), indicating that newly 
born cells may be essential for normal hippocampal functioning.   
 
Several studies suggest that neurogenic areas similar to those described in the rodent 
brain exist in the human brain as well.  For example, Eriksson et al. (17) demonstrated 
that progenitor cells in the human dentate gyrus divide to form new neurons, while Sanai 
et al. (18) found that astrocytes in the human SVZ of the lateral ventricles divide in vivo 
and act as multipotent progenitor cells in vitro.  Human studies have likewise 
demonstrated cognitive deficits following cranial irradiation, most notably in children 
(19-22).  This decline includes diminished capability to learn and memorize new tasks 
and information, as well as a dramatic reduction in full-scale IQ (23).  
 
The relationship between neural precursor cells and the development of GBM remains 
unclear.  There is some evidence that neural progenitor cells may act as precursor cells in 
the development of GBM.  Several animal studies have suggested that gliomas, including 
GBM may be induced from the neural progenitor cells in the subventricular zone (24,25).  
It is therefore possible that sparing these regions during radiation therapy may actually 
result in a worse overall tumor control. 
 
On the other hand, contradictory data suggests that neural progenitor cells may play a 
role in inhibiting tumor growth.  NPCs have been shown to track along and inhibit 
growth of migrating tumor cells and to mitigate tumor-related damage (26-28).  Increased 
NPC attraction to the tumor is associated with decreased tumor size and increased overall 
survival (29).  Recent studies also suggest that radiation may enhance the migration of 
exogenous or endogenous stem cells to site of the tumor.  For example, Tabatabai et al. 
(30) showed that 8 Gy of irradiation increased the tropism of intravenously injected adult 
human hematopoietic progenitor cells to the site of a glioma tumor implanted 
orthotopically in the striatum of a mouse. Less migration was observed in control mice.  
In combination, these data raise the possibility that, in addition to improving long term 
radiation associated toxicity, NPC sparing radiation techniques may potentially contribute 
to improved local control for brain tumors. 
 
Recent human studies have demonstrated that it is possible to use intensity modulated 
radiation therapy (IMRT) to reduce the radiation dose to NPC containing regions during 
radiation therapy for brain tumors (31-33).  In addition, preliminary data using a mouse 


 
 
 
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model has suggested that NPC sparing radiation may allow improved survival of neural 
progenitor cells compared to conventional radiation treatment plans, at least at an early 
time point (34). 
 
Given the potential benefit of NPC in reducing the neurocognitive toxicity of radiation, 
but the unclear relationship between radiation dose to the NPC containing niches and 
tumor control, the purpose of this trial is to examine local recurrence at 1 year using a 
modified radiation technique which attempts to spare the NPC containing niches of the 
brain as much as possible without compromising tumor coverage during adjuvant 
radiation therapy plus temozolomide for GBM.  If this study demonstrates that NPC-
sparing radiation does not adversely influence local recurrence in the spared region of the 
brain, we plan to design a randomized controlled trial to evaluate neurocognitive 
outcomes in brain tumor patients treated NPC-sparing RT versus conventional RT.   
 
2.2 
Temozolomide 
 
 
Temozolomide is an oral alkylating agent that interferes with DNA replication in a 
 
schedule-dependent manner.  The therapeutic benefit of the drug depends on its ability to 
 
alkylate or methylate DNA at the N-7 or O-6 position of guanine residues, which results 
 
in DNA damage and cell death.  Some tumor cells produce an enzyme called O-6-
 
methylguaninine methyltransferase (MGMT) which repairs the DNA damage and 
 
decreases the therapeutic benefit of temozolomide (35).  Epigenetic silencing of MGMT 
 
by some tumor cells prevents synthesis of the enzyme resulting in tumors that are more 
 
sensitive to killing by temozolomide.  Similarly, MGMT presence in GBM cells predicts 
 
for poor response to the drug.  Toxicities associated with temozolomide include nausea, 
 
vomiting,  infertility, teratogenicity, alopecia, fatigue, headache, constipation, anorexia, 
 
convulsions, rash, hemiparesis, diarrhea, asthenias, fever, dizziness, coordination 
 
abnormal, viral infection, amnesia, insomnia, lymphopenia, thrombocytopenia, 
 
neutropenia, and leucopenia,  allergic reactions. 
 
 
2.3 
Correlative Studies Background 
 
Correlative studies include a neurocognitive function test battery that has been validated 
in a multi-institutional phase III study by the Radiation Therapy Oncology Group 
(RTOG) in the context of brain metastases (36,37), plus 1 additional test.  The tests will 
be performed by a trained examiner.  The tests utilized in this protocol are described 
briefly below: 
 
 
 
 
 
 


 
 
 
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2.2.1 Mini Mental State Examination 
 
 
 
 
 
The Mini Mental State Examination (38) is designed to evaluate global 
function.  It consists of six tasks designed to evaluate short term memory 
retention and recall, attention, and language (see Appendix A).  The 
maximum score is 30.  Scores fall into 4 categories: 
 
 
●    24-30: “Normal” range 
 
 
●    20-23: Mild cognitive impairment 
 
 
●    10-19: Moderate cognitive impairment 
 
 
●    0-9: Severe cognitive impairment 
 
 
 
 
2.2.2    Trail Making Test 
 
 
 
 
 
 
The Trail Making Test A is designed to evaluate visual motor scanning speed 
and the Trail Making Test B is designed to evaluate executive function 
(39,40).  These tests require patients to connect circles in numerical (part A) 
or alternating numerical and alphabetical sequence (part B) within a timed 
interval of less than 5 minutes for each test (see Appendix B).  Results are 
reported as the number of seconds required to complete the task with higher 
scores reflecting higher degrees of impairment. 
 
 
Average 
Deficient 
Rule of Thumb 
Trail A 
29 seconds 
>78 seconds 
Most in 90 seconds 
Trail B 
75 seconds 
>273 seconds 
Most in 3 minutes 
 
 
 
 
2.2.3 Controlled Oral Word Association Test 
 
The Controlled Oral Word Association Test (COWAT) is designed to 
evaluate verbal fluency.  It requires patients to name words beginning with a 
specific letter with increasing associated activity, in three 1-minute periods.  
Scoring is based on the number of words named during the 1 minute periods, 
with adjustments for education and age.  Individual scores are categorized as 
intact, low average, borderline, deficient, or seriously deficient, based on their 
scores after these adjustments (41).   
 
 
 
 
2.2.4 Hopkins Verbal Learning Test-Revised 
 
The Hopkins Verbal Learning Test-Revised is designed to evaluate memory.  
It requires patients to memorize a list of 12 items for three consecutive tests 
(recall), to identify the same 12 items from a list of semantically related or 
unrelated items (recognition), and to recall the same 12 items after a 15 
minute delay (delayed recall).  Scoring and interpretation are simple, and 
outlined in a professional manual (42). 


 
 
 
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2.2.5 Digit Symbol Substitution Test 
 
The Digit Symbol Substitution Test (WAIS-IV) is designed to measure 
attention, perceptual speed, motor speed, visual scanning and memory. The 
subject is given a piece of paper with nine symbols corresponding with nine 
digits. Next on this piece of paper are three rows of digits with empty spaces 
below them. The subject is asked to fill in as many corresponding symbols as 
possible in 120 seconds. 
 
3. PATIENT SELECTION 
 
3.1  
Eligibility Criteria 
 
3.1.1 Patient must have newly diagnosed, histologically confirmed GBM. 
 
 
 
 
3.1.2 Patient must have undergone gross total resection, subtotal resection, or 
biopsy with the extent of resection determined by the treating neurosurgeon, 
and must begin radiation within 12 weeks of this procedure. 
 
3.1.3    Patients must not have received previous irradiation to the brain. 
 
3.1.4    Patient must be at least 18 years of age since the diagnosis of GBM in patients  
younger than 18 is rare and accurate evaluation of neurocognitive function 
would require a different battery of examinations than employed in this study. 
 
3.1.5 ECOG performance status  (Karnofsky 60%; see Appendix A). 
 
3.1.6 Patient must be scheduled to receive temozolomide concurrent with and 
following radiation (temozolomide may be started late due to insurance 
reasons, insufficient counts, or other reasons) 
 
3.1.7 If a woman is of child-bearing potential, a negative urine or serum pregnancy 
test must be demonstrated prior to treatment. Women of childbearing potential 
and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) for the duration of study participation and 
for up to 12 weeks following the study. Should a women become pregnant or 
suspect she is pregnant while participating in this study she should inform her 
treating physician immediately. 
 
3.1.8 Patient must have the ability to understand and the willingness to sign a 
written informed consent document.   
 
3.1.9    All patients must be informed of the investigational nature of this study and 
must be given written informed consent in accordance with institutional and 
federal guidelines. 
 
 
 


 
 
 
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3.2  
Exclusion Criteria 
 
3.2.1 Patients may not receive any approved or investigational agents to treat their 
glioblastoma besides temozolomide.  
 
 
Note: Exceptions may be made for non-therapeutic intervention at the 
discretion of the Principal Investigator.  
 
3.2.2 No prior malignancy is allowed except for adequately treated basal cell or 
squamous cell skin cancer, cervical carcinoma in situ, or other cancer from 
which the patient has been disease free for at least 2 years. 
 
3.2.3 Patients with uncontrolled intercurrent illness including, but not limited to, 
ongoing or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements will be excluded. 
 
3.2.4 Pregnant and breastfeeding women are excluded. Women of child-bearing 
potential who are unwilling or unable to use an acceptable method of birth 
control to avoid pregnancy for the entire study period and up to 12 weeks after 
the study are excluded. This applies to any woman who has not experienced 
menarche and who has not undergone successful surgical sterilization or is not 
postmenopausal (defined as amenorrhea for at least 12 consecutive months). 
Male subjects must also agree to use effective contraception for the same 
period as above. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.   
 
4. REGISTRATION PROCEDURES 
 
Patients will be accrued from Johns Hopkins Medical Institutes in Baltimore, MD.  Contact 
information for the Principal Investigator is listed on the cover page.   
 
To register the patient, the following documents must be completed and faxed to 410-502-
2821 or emailed to Katharine Oteiza, the Study Coordinator at koteiza1@jhmi.edu.   
 
 Copy of operative note and pathology report 
 Source documentation verifying eligibility 
 Eligibility checklist 
 Signed patient consent form 
 HIPAA authorization form 
 
If the patient is deemed eligible for the study, the Study Coordinator will register the patient 
and assign a study number. 


 
 
 
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Adjuvant radiation therapy must begin within 12 weeks of surgery. 
 
5. TREATMENT PLAN 
 
5.1  Surgery and Chemotherapy 
 
5.1.1 Surgical considerations  
 
As an eligibility requirement patients must undergo maximal safe resection, 
with the extent of resection determined by the treating neurosurgeon. 
 
5.1.2 Chemotherapy   
 
Patients will be scheduled to receive continuous daily temozolomide (75 mg 
per square meter of body surface area per day, 7 days per week from the first 
to the last day of radiation therapy), followed by 6 cycles of adjuvant 
temozolomide (150 to 200 mg per square meter for 5 days during each 28 day 
cycle).Temozolomide may be started later than the first day of radiation 
therapy due to insurance reasons, insufficient counts, or other reasons. 
Temozolomide may be held, discontinued, or modified at the discretion of the 
treating medical oncologist. Laboratory studies such as CBC with differential 
and comprehensive metabolic panels will be performed at the discretion of the 
patient’s medical oncologist.   At the time of tumor progression or after one 
year of follow-up, further chemotherapy or biologic therapy is permitted at the 
provider’s discretion.  Therapy will be recorded, but the patient will not be 
removed from the study.   
 
5.2 
Radiation  
 
5.2.1 Radiation Simulation and Prescription 
 
 
Patients will be treated to a total dose of 60 Gy with a once daily fractionation 
schedule of 2 Gy per fraction, administered five days per week.  All patients 
will undergo CT simulation with intravenous contrast.  In addition they will 
undergo MRI simulation with both T1 with gadolinium as well as FLAIR 
sequences.  They will be treated in a supine position using an aquaplast mask 
system for immobilization.  CT image data will be reconstructed in 
approximately 3 mm slice thickness and manually coregistered with T1 post-
gadolinium and FLAIR sequence MRI.   
 
5.2.2 Target Delineation 
 
Delineation of the tumor and treatment margins will follow the Johns Hopkins 
institutional standard and will not be altered in any way for the purpose of this 
study.  The gross tumor volume-1 (GTV-1, initial field) will be contoured 
using the simulation CT scan and fused T1 with gadolinium and FLAIR 


 
 
 
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sequence MRI.  The gross tumor volume-2 (GTV-2, cone down field) will be 
contoured using the simulation CT scan and the T1 with gadolinium sequence 
MRI.  The clinical tumor volume (CTV) will include the respective GTV plus 
approximately 0.5 to 1 cm margin.  The planning tumor volume (PTV) will 
include the respective CTV plus approximately 0.5 cm margin.   
 
5.2.3 Normal Tissues 
 
Organs at risk including the eyes, lens, optic nerves, optic chiasm, brainstem,  
spinal cord, and inner ears will be contoured on the planning CT scan.  Target 
dose constraints on these organs will follow the institutional standards at 
Johns Hopkins:   
 
 
Organ 
Volume 
Dose Constraint 
Spinal Cord 
0.1 cc 
Max 50 Gy 
Brainstem 
0.1 cc 
Max 62 Gy 
Chiasm 
0.1 cc 
Max 55 Gy 
Optic Nerve 
0.1 cc 
Max 55 Gy 
 
5.2.4    Neural Progenitor Cell Containing Niches 
 
The NPC containing niches will be defined as a 5 millimeter region adjacent 
to the lateral wall of the lateral ventricle and the entire hippocampus.  These 
areas will be contoured on the simulation CT scan using a manually 
coregistered MRI as a reference.  A portion of the NPC-containing niches 
which is >2 cm from the PTV will be contoured as a region of interest and 
labeled as “NPC_for_sparing”.  A radiation treatment plan will be generated 
in which we attempt to limit the RT dose to the “NPC_for_sparing” region as 
much as possible without compromising the radiation dose coverage of the 
tumor.  Specifically, using inverse planning, the dose constraint and weight of 
the “NPC_for_sparing” region will be progressively tightened until additional 
iterations would to result in compromised tumor coverage or unacceptable 
dose to another organ at risk.  The extent of NPC sparing that is possible will 
be recorded for each patient in terms of the volume of the “NPC_for_sparing” 
region, and the mean, minimum, and maximum dose to this area.  .   
 
                  5.2.5    Equipment, Radiation Technique, and Dosimetry 
 
Patients will be treated using a megavoltage linear accelerator with nominal 
beam energy of 6 MV and cone beam CT guidance for precise localization.  
Dosimetric indicators of plan quality such as the minimal dose to the PTV, 
conformity index, D50 to the whole brain as a measure of integral dose, and 
dose to the normal structures will be recorded. 
 
5.2.6 Beam Verification 
 
Either daily on-line cone beam CT guidance or weekly portal imaging will be 


 
 
 
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used for precise patient setup. 
 
 
 
5.2.7 Therapy Interruption 
 
For radiation therapy interruptions of up to and including 14 days, irradiation 
should be completed to the full prescribed dose.  On the last day, the total 
number of fractions and the reasons for interrupting therapy must be 
documented. 
 
If radiation therapy interruption goes beyond 14 days, the patient will be 
removed from the protocol treatment.  Resumption and completion of 
treatment will then be at the discretion of the radiation oncologist in 
consultation with the principal investigator.  All patients who initiate protocol 
treatment will be followed per the study calendar. 
 
 
5.2.8 Risks of Radiation 
 
       
      Short term toxicities of radiation therapy include fatigue, alopecia,    
                  erythema or irritation of the skin, dry skin, headaches, worsening of current  
                  symptoms, edema of brain requiring steroids, ear pain or discomfort, damage  
                  to the baby if patient is or becomes pregnant, seizures, neurologic deficits  
                  depending on tumor location, edema of brain requiring surgery, death.  Long  
                  term toxicities include memory loss, cataracts, edema of the brain requiring  
                  steroids, vision loss, hearing loss, necrosis of brain  requiring surgery 
 
                  second tumor or cancer caused by radiation. 
 
5.3 Duration of Follow Up 
 
Patients will be followed either at Johns Hopkins Hospital or an outside facility until 
death or the time of data analysis.  It is preferred that MRIs be performed at Johns 
Hopkins Hospital but they may also be performed at outside facilities as necessary for 
insurance, scheduling, or other reasons. 
 
5.4 Criteria for Removal from Study 
 
 
Patients will be removed from the study for the following reasons: 
 
5.4.1 Unacceptable toxicity from therapy.  Toxicity must be appropriately 
documented. 
 
5.4.2 Development of intercurrent, non-cancer related illness that prevents either 
continuation of therapy or regular follow-up. 
 
5.4.3 The patient may decide to discontinue enrollment in the protocol at any time 
and for any reason.   
 
 
            All reasons for discontinuation of treatment must be documented.  The decision to   


 
 
 
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                  continue either treatment modality while discontinuing the other (i.e.: discontinue  
                  radiation while continuing temozolomide) must be discussed with the principal  
                  investigator and treating physician(s).  
 
6. 
STUDY CALENDAR 
 
Baseline evaluations are to be conducted prior to initiation of adjuvant radiation therapy.  
Patients will be evaluated with a toxicity assessment at least weekly during the course of 
radiation therapy.  Note that the study calendar is based on the ideal subject.  The schedule 
should be followed as closely as realistically possible, but may be modified due to problems 
such as scheduling delays, conflicts such as clinic closure or poor weather conditions, or 
other unforeseeable events.  Neurocognitive testing will be obtained after 12 months only if 
funding allows.  Follow-up MRIs will be obtained as medically indicated by the patient’s 
provider.  
 
 
  
Baseline1 
Treatment (Weeks) 
Follow-Up 
(Post-RT) 
1 
2 
3 
4 
5 
6 
6 
Mo 
12 
Mo 
24 
Mo 
Demographics 
X 
  
  
  
  
  
  
  
  
  
Medical history 
X 
  
  
  
  
  
  
  
  
  
Physical Exam 
X 
  
  
  
  
  
  
X 
X 
X 
Vital signs11 
X 
  
  
  
  
  
  
  
  
  
Weight 
X 
  
  
  
  
  
  
  
  
  
Pregnancy Test2 
X 
  
  
  
  
  
  
  
  
  
Performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Labs3 
X 
X 
X 
X 
X 
X 
X 
  
  
  
Neurocognitive 
testing4 
X 
  
  
  
  
  
  
X 
X 
X 
Toxicity 
Assessment 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Acute toxicity5 
X 
X 
X 
X 
X 
X 
X 
  
  
  
Late toxicity6 
  
  
  
  
  
  
  
X 
X 
X 
Brain MRI 
 
  
  
  
  
  
  
X 
X 
X7 
CT Scan8 
X 
  
  
  
  
  
  
  
  
  
Chemotherapy9 
  
X 
X 
X 
X 
X 
X 
X 
  
  
Radiation10 
  
X 
X 
X 
X 
X 
X 
  
  
  
1Baseline evaluations are to be conducted prior to initiation of adjuvant radiation therapy 
2If a woman is of child-bearing potential, a negative urine or serum pregnancy test must be 
demonstrated prior to treatment. 


 
 
 
11 
Version: April 1st, 2014 
3Laboratory tests to be performed at baseline include CBC with differential and CMP.  Week 1-6 
laboratory tests include CBC with differential and CMP will be performed at the discretion of the 
patient's medical oncologist. 
4The Mini Mental State Examination, Trail Making Test A&B, Controlled Oral Word Association 
Test, Hopkins Verbal Learning Test Revised Digit Symbol Substitution Test 
5RTOG Acute Morbidity Scoring Criteria 
6RTOG Late Morbidity Scoring Criteria 
7After 12 months follow-up MRI will be obtained only as deemed medically indicated by the 
patients provider 
8CT simulation with intravenous contrast, data will be reconstructed in 3 mm slice thickness and 
manually coregistered with T1 post-gadolinium and FLAIR sequence MRI 
9Patients will be scheduled to receive continuous daily temozolomide (75 mg per square meter of 
body surface area per day, 7 days per week from the first to the last day of radiation therapy), 
followed by 6 cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during 
each 28 day cycle).Temozolomide may be started later than the first day of radiation therapy due to 
insurance reasons, insufficient counts, or other unknown reasons. Temozolomide may be held, 
discontinued, or modified at the discretion of the treating medical oncologist.  
10Patients will be treated with a total dose of 60 Gy with a once daily fractionation schedule of 2 Gy 
per fraction 
11BP, P, R, Temperature 
 
 
7. MANAGEMENT OF TOXICITY 
 
      7.1  
Acute Toxicity 
 
 
 
Acute morbidity potentially associated with therapy will be monitored and recorded 
on the Radiation Oncology On-Treatment Evaluation Form for all patients from 
baseline to 3 months after completion of radiation therapy.  Grading will be according 
to the RTOG Acute Morbidity Scoring Criteria as follows: 
 
 
Organ 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Skin 
No change 
over 
baseline 
Faint 
erythema, 
epilation, dry 
desquamation, 
or decreased 
sweating 
Tender or 
bright 
erythema, 
patchy moist 
desquamation, 
moderate 
erythema 
Confluent, 
moist 
desquamation 
other than skin 
folds, pitting 
edema 
Ulceration, 
hemorrhage, 
necrosis 
Eye 
No change 
over 
baseline 
Mild 
conjunctivitis 
with or 
without 
scleral 
Moderate 
conjunctivitis 
with or 
without 
keratitis 
Severe keratitis 
with corneal 
ulceration, 
objective 
decrease in 
Loss of vision 
(unilateral or 
bilateral) 


 
 
 
12 
Version: April 1st, 2014 
Organ 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
injection, 
increased 
tearing 
requiring 
steroids 
and/or 
antibiotics, 
dry eye 
requiring 
artificial tears, 
iritis with 
photophobia 
visual acuity or 
in visual fields, 
acute 
glaucoma, 
panopthalmitis 
Ear 
No change 
over 
baseline 
Mild external 
otitis with 
erythema, 
pruritis, 
secondary to 
dry 
desquamation 
not requiring 
medication.  
Audiogram 
unchanged 
over baseline. 
Moderate 
external otitis 
requiring 
topical 
medication, 
serous otitis 
media, 
hypoacusis on 
testing only 
Severe external 
otitis with 
discharge or 
moist 
desquamation, 
symptomatic 
hypoacusis, 
tinnitus, not 
drug related 
Deafness 
CNS 
No change 
over 
baseline 
Fully 
functional 
status with 
minor 
neurologic 
findings, no 
medications 
needed 
Neurologic 
findings 
present 
sufficient to 
require home 
care.  Nursing 
care may be 
required.  
Medications 
including 
steroids 
and/or anti-
seizure agents 
Neurologic 
findings 
requiring 
hospitalization 
for initial 
management 
Serious 
neurologic 
impairment 
which included 
paralysis, 
coma, or 
seizures, 
despite 
medications.  
Hospitalization 
required 
Hematologic 
WBC 
(x1000) 
≥ 4.0 
3.0 - <4.0 
2.0 - <3.0 
1.0 - <2.0 
<1.0 
Platelets 
(x 1000) 
≥ 100 
75 - <100 
50 - <75 
25 - <50 
<25 or 
spontaneous 
bleeding 
Neutrophils 
≥ 1.9 
1.5 - <1.9 
1.0 - <1.5 
0.5 - <1.0 
<0.5 or sepsis 
Hematocrit 
(%) 
≥ 32 
28 - <32 
<28 
Packed cell 
transfusion 
required 
N/A 
 
 


 
 
 
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14 
Version: April 1st, 2014 
7.2 
 
Late Toxicity 
 
Late toxicity will be recorded on the Radiation Oncology Follow-up form at each 
follow-up visit greater than 3 months post completion of radiation therapy.  Grading 
will be according to the RTOG Late Radiation Morbidity Scoring Schema as follows: 
 
Organ 
Grade 
0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 
5 
Skin 
None 
Slight 
atrophy, 
pigmentation 
change, some 
hair loss 
Patchy 
atrophy, 
moderate 
telangiectasia, 
total hair loss 
Marked 
atrophy, gross 
telangioectasia 
Ulceration 
Death directly related to late radiation effect 
Subcutaneous 
Tissue 
None 
Slight 
induration 
and loss of 
subcutaneous 
fat 
Moderate 
fibrosis but 
asymptomatic
.  Slight field 
contracture.  
<10% linear 
reduction 
Severe 
induration and 
loss of 
subcutaneous 
tissue.  Field 
contracture 
>10% linear 
measurement 
Necrosis 
Spinal Cord 
None 
Mild 
L’Hermitte’s 
syndrome 
Severe 
L’Hermitte’s 
syndrome 
Objective 
neurologic 
findings at or 
below cord 
level treated 
Mono-, para-, 
quadra-plegia 
Brain 
None 
Mild 
headache, 
slight 
lethargy 
Moderate 
headache, 
great lethargy 
Severe 
headaches, 
severe CNS 
dysfunction 
(partial loss of 
power or 
dyskinesia) 
Seizures, 
paralysis, coma 
Eye 
None 
Asymptomati
c cataract, 
minor corneal 
ulceration of 
keratitis 
Symptomatic 
cataract, 
moderate 
corneal 
ulceration, 
minor 
retinopathy or 
glaucoma 
Severe 
keratitis, 
severe, 
retinopathy or 
detachment, 
severe 
glaucoma 
Panopthalmitis, 
blindness 
 
 
 
 


 
 
 
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Version: April 1st, 2014 
8. 
STATISTICAL CONSIDERATIONS 
 
8.1 Study Design/Endpoints 
 
 
 
 
 
8.1.1  Study Design 
This is a single arm prospective investigation to evaluate the local recurrence 
rate in the spared NPC-containing regions of the brain after NPC-sparing 
radiation therapy plus temozolomide for newly diagnosed GBM. 
 
8.1.2 Primary Endpoint 
Site of local recurrence at 1 year post radiation therapy will be recorded for 
each patient.  Sites will be classified as follows: 1) Recurrence within the 
spared NPC-containing region, defined as a recurrence within the avoidance 
structure contoured on the simulation CT scan; 2) Recurrence outside of the 
spared NPC-containing region, defined as a recurrence that is not within this 
avoidance structure; 3) No local recurrence. 
 
8.1.3 Secondary Endpoints 
 
 
 
      8.1.3.1      The extent of NPC-sparing will be recorded for each  
                                                patient.  Patients will be binned into 4 groups according to the  
                                                volume of NPC region that receives a certain dose as follows: 1)               
                                                V5Gy≤50%; 2) V5Gy ≤20%; 3) V10Gy≤20%; 4) Doses higher than  
                                                levels 1-3.   
 
8.1.3.2 
The X-, Y-, and Z- coordinate distances in centimeters will be 
recorded from the most proximal point of the planning tumor 
volume to the closest point of the spared NPC-containing niche.  
The mean, minimum, and maximum radiation dose to the spared 
NPC-containing region will be recorded for each patient.  In 
addition, the volume of the “NPC_for_sparing” region will be 
recorded.   
 
8.1.3.3       Completion of  neurocognitive testing and Neurocognitive function 
 
 
 
will be assessed at baseline, and at six, twelve, and twenty-four  
 
 
 
months from baseline using the Mini Mental State Exam, Trail  
 
 
 
Making Test A & B, Controlled Oral Word Association Test,  
 
 
 
Hopkins Verbal Learning Test-Revised and the Digit Symbol  
 
 
 
Substitution Test. 
 
 
 
 


 
 
 
16 
Version: April 1st, 2014 
8.2 Sample Size/Accrual Rate 
 
 
 
 
8.2.1  Sample Size 
 
 
The required sample size is based upon the primary study hypothesis which is the 
rate of local recurrence within the spared NPC-containing region at 1 year post 
radiation therapy in patients treated with NPC sparing RT plus temozolomide for 
newly diagnosed GBM.  Using conventional RT, approximately 20% of GBM recur 
outside of the tumor bed or radiation field margin (48).   We hypothesize that there 
will be ≤25% LR rate in the designated NPC avoidance region using our modified 
radiation technique, which is clinically acceptable.  This is the first study to estimate 
the LR rate in the spared NPC containing region following NPC sparing RT for 
GBM.  Given the clinically meaningful control LR rate in this region of 25% and a 
moderate variation among the patients, the 30 patients will have the optimal 
information gain (relative certainty) based on empirical information entropy to 
estimate the LR rate in the spared region (49).  
 
        8.2.2  Accrual 
 
We anticipate enrollment of approximately 3-4 patients per month to the protocol 
with accrual completed in approximately 1-2 years.   
 
8.3   Stratification Factors 
 
 
 
 
There will be no stratification factors upon initial enrollment in the protocol.   
 
    8.4 Statistical Methods of Analysis 
 
All analysis will be based on the Intend-To-Treat (ITT) principle. Per-protocol will be 
allowed after ITT analyses. 
 
The proportion of patients with LR in the avoidance region of the NPC will be 
estimated along with the exact 95% confidence interval.  The lower bound 95% 
confidence interval of exact binomial distribution will be used to determine the 
acceptance of the LR rate of 25%. 
 
All patients will count towards assessment of all objectives.  However, if no patient 
relapses in the spared NPC containing region, we recognize that the present study 
will not definitively demonstrate that sparing of the NPC regions does not impact 
the pattern of recurrence since this is a pilot study and 2 patients received 
mebendazole following completion of radiation therapy but prior to relapse.  Given 
that no intervention to date including systemic agents, radiation dose escalation, and 
hypofractionation has ever impacted the site of recurrence we feel it is exceedingly 
unlikely that mebendazole would impact our primary endpoint.  However, we will 
evaluate if the analysis of the primary endpoint would yield different results with 
or without inclusion of these patients.  If there is a difference both analyses will be 
presented in the manuscript.  Even if there is no statistically significant difference 


 
 
 
17 
Version: April 1st, 2014 
between the groups we will clearly state in our publications that 2 patients received 
mebendazole with their adjuvant temozolomide following completion of radiation 
therapy but prior to relapse.  
 
To quantify the extent of radiation dose sparing to the NPC containing regions that is 
possible, patients will be binned into 4 groups according to the volume of NPC region 
that receives a certain dose as follows: 1) V5Gy≤50%; 2) V5Gy ≤20%; 3) V10Gy≤20%; 4) 
Doses higher than levels 1-3.  The proportion of overall patients who meet at least the 
dose constraint will be estimated using a binomial distribution along with 95% 
confidence intervals, as well as the individual group.  
 
To assess the feasibility of evaluating cognitive function prospectively in this patient 
population, we will evaluate the six month post radiation therapy protocol compliance 
in terms of neuropsychological evaluations.  The proportion of patients completing the 
planned neurocognitive assessments at both baseline and 6 months post radiation 
therapy will be calculated, along with the 95% confidence interval.  If ≥40% of patients 
did not complete at least 1 of these planned assessments, the testing will be considered 
not feasible. 
 
The change in neurocognitive function from baseline to 6 months post radiation 
therapy will be explored by using the 5 instruments measuring neurocognitive 
function .  The change will be summarized graphically (using, for example, boxplots) 
and using mean, median or score shifting etc. This will be done for each instrument 
separately. Correlation coefficients will be calculated to explore potential correlation 
between the change in neurocognitive function from the baseline and the radiation 
dose to the NPC-containing region.  
 
Spearman’s rank correlation coefficient will be calculated to explore an association 
between the closest distance (either X-, Y-, or Z-) of the planning tumor volume to 
the spared NPC-containing niche and the mean, minimum, and maximum radiation 
dose to this region.   
 
 
  8.5     Interim Disease Progression Monitoring 
 
 
   
      Based on the unpublished data from the New approaches to Brain Tumor Therapy  
      Consortium, the median time of progression was 8.5 months among the newly  
      diagnosed GBM treated by RT+TMZ (standard). The progression area outside  
      radiation bed was about 20%. This study does not anticipate an above 30%  
      progression rate in the spared NPC containing region. We expect a less than 30%,  
      about 20% progression rate in the spared NPC containing region. However, we plan  
      to monitory the progression rate throughout the trial.   The progression rate in the  
      spared NPC containing region will be monitored continuously throughout the cohort  
      using the Bayesian stopping rule at patient numbers 10 and 20, after patients have a  
      minimum of 6 months follow-up. We consider a 30% progression rate the highest  
      limit that permits to continue this study and will stop early if there are excesses. The  
      number of patients experiencing progression in the spared NPC containing region was  
      assumed to follow a binomial distribution. Given the planned sample size of 30, a  


 
 
 
18 
Version: April 1st, 2014 
      stopping boundary would be reached if the proportion of patients experiencing  
      progression in the spared NPC containing region exceeds 30% with a posterior  
      probability ≥ 0.6.  A recommendation for early stopping if 4 or more out of 10, or 7  
      or more out of 20 patients had disease progression in the spared NPC containing  
      region. The probability of meeting the stopping boundary is 0.56 under a true  
      probability of progression is 0.3.  
 
 
 
 


 
 
 
19 
Version: April 1st, 2014 
9. ADVERSE EVENTS AND RECORDING  
 
9.1 
Definition of Adverse Event (AE) 
 
 
      
      An adverse event is the development of an undesirable medical      
      condition or the deterioration of a pre-existing medical condition during or following           
      an exposure to a treatment, whether or not considered causally related to the      
      treatment.  An undesirable medical condition may be symptoms (headache, nausea),          
      signs (tachycardia, enlarged liver), or abnormal results of an investigation (MRI,   
      laboratory finding).  In clinical trials, from the time of signing an informed consent,   
      an AE may include an undesirable medical condition, occurring at any time, even if  
      no trial treatment has been administered. 
 
 
9.2       Radiation Related Adverse Events  
 
Risks Associated with Brain Radiation Therapy: 
 
Very Likely 
 Scalp redness or soreness 
 Hair loss 
 Dry mouth or altered taste 
 Fatigue, sleepiness 
 Skin redness or soreness in the ear canal 
 
Less Likely, But Serious 
 Permanent hair loss 
 Hearing loss 
 Eye injury resulting in vision loss or even blindness 
 Mental slowness, behavioral changes 
 Severe damage to normal brain tissue that may require additional surgery 
 Brain damage, which could affect judgment, memory, sensation, or ability to 
control movement 
 
Less Likely 
 Fever, chills, heavy sweating 
 Upset stomach, nausea and/or vomiting 
 Loss of appetite 
 Headaches, seizure, weakness 
 
All radiation related adverse events will be recorded on the local toxicity case report 
forms. 
 
     
 
 


 
 
 
20 
Version: April 1st, 2014 
  9.3 
Chemotherapy Related Adverse Events 
 
Risks associated with Temozolomide: 
 
Very Likely 
 Nausea and/or vomiting 
 Headache 
 Constipation 
 Drowsiness/Fatigue 
 Insomnia (trouble sleeping) 
 Skin rash 
 Swelling 
 
Less Likely, But Serious 
 Decrease in blood counts that may cause infection and bleeding 
 Decreased ability to carry out daily activities 
 Pneumonia 
 Increased blood sugar 
 Pain when swallowing 
 Internal bleeding 
 Seizure 
 Subsequent development of leukemia 
 
Less Likely 
 Loss of appetite 
 Diarrhea 
 Fever 
 Weight loss 
 Weakness 
 Sores in your mouth 
 Hair loss 
 Weakness of hands and feet 
 A temporary elevation in the blood tests that show how your liver is functioning 
 Shortness of breath 
 Confusion 
 Blurred vision 
 Allergic reactions 
 Chills 
 Body aches 
 Coughing 
 
The adverse events (both hematologic and non-hematologic) that patients experience 
due to chemotherapy will be recorded on appropriate case report forms only if they 
are greater than or equal to grade 3, result in a delay in treatment, or are required to be 
reported per institutional guidelines.   


 
 
 
21 
Version: April 1st, 2014 
10. SERIOUS ADVERSE EVENTS (SAE) AND REPORTING 
 
10.1     Serious Adverse Event 
 
10.1.1 Definition of Serious Adverse Event 
 
A serious adverse event is an AE occurring at any point during a clinical trial that 
fulfills one or more of the following criteria: 
 
 
● Results in death. 
 
 
● Is immediately life threatening. 
 
 
● Requires in-patient hospitalization or prolongation of existing 
hospitalization. 
 
 
● Is a congenital abnormality or birth defect. 
 
● Unexpected event that cause harm or place person at a greater risk of harm 
than was previously known or recognized, and which was possibly related 
to the research.  Unexpected means that the event was not described in the 
consent form or the event exceeded the expected severity. 
 
● Is an important medical event that may jeopardize the patient or may 
require medical intervention to prevent one of the outcomes listed above. 
 
10.2      SAE Reporting Guidelines for Johns Hopkins Hospital 
 
All SAE, with the exception of death, must be reported to the Johns Hopkins Hospital 
Institutional Review Board (JH-IRB) within 10 working days of the principal 
investigator learning of the event.  Reporting for the death of a patient which was 
unexpected (i.e.: not related to a risk of participation that was listed in the protocol or 
the consent document, and was more likely than not to be caused by the research 
procedure/intervention, must be reported to the JH-IRB within 3 working days of 
when the principal investigator receives the report of the death.  Reporting for death 
of a participant that was expected due to the nature of the patient’s underlying disease 
or condition, or identified as caused by a possible risk of the study 
procedure/intervention as described in this protocol or consent form, must be reported 
to the JH-IRB within 10 working days from the time the principal investigator learns 
of the event.  If death occurs 30 days after the participant has stopped or completed 
their study treatment, the principal investigator does not have to report the death until 
the time of continuing review.   
 
 
 


 
 
 
22 
Version: April 1st, 2014 
11.    DATA AND SAFETY REPORTING/ REGULATORY CONSIDERATIONS 
 
 
11.1  Data Quality Monitoring 
 
In addition to the ongoing quality assurance evaluations for each individual at the 
time of treatment, there will be regular internal monitoring meetings between the 
principal investigator, a medical oncologist, and the study coordinator to assess the 
data quality.  These meetings will occur annually and a monitoring report of the 
findings will be submitted to the Data Safety Monitoring Committee on an annual 
basis.  Any protocol deviations or violations will be documented in the monitoring 
reports.  The review will include: consent forms, eligibility criteria, protocol 
compliance, treatment administration, toxicity reports, response, regulatory 
compliance, case report forms (completeness as well as verifying that information 
coded on the case report forms are supported by source documents), and all other 
materials related to the trial.  This is a Level I study under the SKCCC Data 
Monitoring Plan (6/26/2010).  The Clinical Research Office QA group will assume 
external auditing responsibilities by performing an audit at the end of the first year 
and then periodically thereafter depending on the rate of accrual and prior audit 
results.  The Safety Monitoring Committee will review this trial for safety and data 
quality annually. 
 
 
11.2   Data Safety Monitoring 
 
All SAE’s and major protocol deviations that occur at Johns Hopkins Hospital will be 
submitted to the IRB of record. Once in the IRB these reports of SAEs and major 
protocol deviations will be reviewed by the Sidney Kimmel Comprehensive Cancer 
Center Data Monitoring Committee (SMC) for review per Institutional guidelines.  In 
addition, the overall study safety and potential activation of the study’s early stopping 
rules will be assessed at the time of every SAE.  The Data Safety Monitoring 
Committee with review this trial for safety annually.  
 
 
11.3 
Data Reporting 
 
11.3.1 
Method 
 
 
 
 
 
 
 
 
 
Data will be collected on Case Report Forms (CRFs). These CRFs will be   
 
 
 
 
 
completed by the study coordinator. The CRFs for each subject will be kept in  
 
 
 
 
a separate  research binder. Along with each completed CRF there will be   
 
 
 
 
 
corresponding source documentation filed for verification. The Principal   
 
 
 
 
 
Investigator, Research Study Nurse, and Study Coordinator will informally  
 
 
 
 
 
meet on a regular basis to make sure that the trial is progressing as mandated   
 
 
 
 
by the protocol. The CRO will audit this trial per their standards to ensure   
 
 
 
 
 
and verify that the protocol is be carried out according to specs as well as to   
 
 
 
 
verify that data included on subject CRFs are accurate. Exit reports generated   
 
 
 
 
as a result of these CRO audits will be forwarded to both the Safety  
 
 
 
 
 
 
 
Monitoring Committee as well as to the adjudicating IRB of record for review. 


 
 
 
23 
Version: April 1st, 2014 
 
 
11.3.2      Responsibility for Submissions 
 
Not applicable. 
 
11.4 
CTEP Multicenter Guidelines 
 
Not applicable. 
 
11.5 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA) 
 
Not applicable 
 
 
 
 


 
 
 
24 
Version: April 1st, 2014 
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APPENDIX A 
 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead.