A Phase II Trial of Low Dose Fractionated Radiation Therapy as a Chemo-Potentiator of Salvage Temozolomide for Recurrent Anaplastic Astrocytoma and Glioblastoma Multiforme
Phase: PHASE2
Conditions: High Grade Glioma
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

September 29, 2022 
 
i 
NCT01466686 
 
 
A Phase II Trial of Low Dose Fractionated Radiation Therapy as a Chemo-Potentiator of Salvage 
Temozolomide for Recurrent Anaplastic Astrocytoma and Glioblastoma Multiforme 
 
September 29, 2022 
 
 

September 29, 2022 
 
ii 
TITLE:  A Phase II Trial of Low Dose Fractionated Radiation Therapy as a Chemo-Potentiator 
of Salvage Temozolomide for Recurrent Anaplastic Astrocytoma and Glioblastoma Multiforme 
 
Coordinating Center: 
The Johns Hopkins University School of Medicine 
 
*Principal Investigator: 
Kristin 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 
 
Jaishri Blakely, M.D., Department of Oncology 
 
Matthias Holdhoff, M.D., Department of Oncology 
 
John Laterra, M.D., Ph.D., Department of Neurology 
 
Brandi Page, M.D., Department of Radiation Oncology 
 
 
 
 
Statistician: 
 
Chen Hu 
 
 
 
 
Telephone: 410-614-3508 
 
Email:  huc@jhu.edu 
 
Research Manager: 
Dana Kaplin 
410-614-3950 
dkaplin1@jhmi.edu 
 
Study Coordinators: 
Katie Lowe                                   James Huang  
 
 
 
 
 
 
410-955-8652                               410-955-8656                          
 
 
 
 
katielowe@jhmi.edu  
 
jhuan136@jhmi.edu   
 
 
 
 
 
 
Research Nurses: 
 
Jessica Leitzel, R.N.                    Shirl DiPasquale, R.N.  
 
 
410-502-9242                              410-614-1598 
 
 
 
 
Jvogel10@jhmi.edu   
     sdipasq1@jhmi.edu 
 
 
 
  
 
 
 

September 29, 2022 
 
iii 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For the purpose of this clinical trial High Grade Glioma (HGG) will only include Anaplastic Astrocytoma and 
Glioblastoma Multiforme. 
2) Is long term radiation-
associated toxicity of 
salvage LDFRT + 
temodar acceptable? 
Future Proposal:  
Randomized 
prospective trial of 
salvage LDFRT + 
temodar vs. temodar 
alone for recurrent  
high grade glioma 
(HGG) OR adjuvant 
LDFRT+ temodar in 
newly diagnosed HGG 
This concept should 
go no further 
1) Is 1 year OS >28.6%  
 
2) Is grade 3 and 4 hematologic 
toxicity < 33%? 
No 
Yes 
Salvage temodar + low dose 
fractionated radiation (LDFRT) 
Enrollment 
Recurrent High Grade Glioma (HGG) 
s/p surgery followed by RT + temodar  
1) Is 1 year overall 
survival (OS) better than 
expected for salvage 
temodar alone?  

September 29, 2022 
 
iv 
TABLE OF CONTENTS 
 
Page 
SCHEMA........................................................................................................................................ii  
 
1. OBJECTIVES 
………..…………………………………………………………………. .1 
      1.1       Safety Run In ……...…………..…………………………………………………….1 
1.2 
Phase II …………..………………………………………………………………….1 
 
2. BACKGROUND …………………………………………………………………………….1 
2.1  
Study Disease ...............................................................................................................1 
2.2       LDFRT Rationale ………............................................................................................2 
2.3  
Temozolomide………………………………………………………………………..3 
2.4  
Correlative Studies Background  …………………………………………………..3 
 
3. PATIENT SELECTION.........................................................................................................3 
3.1  
Eligibility Criteria .…………………………………………………………………..3 
3.2  
Exclusion Criteria……………………………………………………………………5 
3.3  
Inclusion of Women and Minorities ………………………………………………..5 
 
4. REGISTRATION PROCEDURES .………………………………………………………..5 
 
5. TREATMENT PLAN……………….……………………………………………………….6 
5.1  
Temozolomide …………………………………………………………………….... 6 
5.2  
Low Dose Fractionated Radiation Therapy (LDFRT) …………………………....6 
5.3  
Duration of Therapy…………………………………………………………………8 
5.4 
Duration of Follow Up .................................................................................................8 
5.5 
Criteria for Removal from Study ..............................................................................9 
 
6. CORRELATIVE/SPECIAL STUDIES ……………………………………………………9 
 
7. STUDY CALENDAR ……………………………………………………………………….9 
 
8. MEASUREMENT OF EFFECT……………………………………………………………9 
8.1 
Antitumor Effect..........................................................................................................9 
 
9. STATISTICAL CONSIDERATIONS ……………………………………………………13 
9.1 
Study Design/Endpoints ..………………………………………………………….13 
9.2 
Sample Size/Accrual Rate …………………………………………………………15 
 
9.3  
Statistical Methods of Analysis ……………………………….…………………...17 
 
10. ADVERSE EVENTS AND RECORDING .........................................................................17 
 
10.1 
Definition of Adverse Event AE)..............................................................................17 

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10.2 
Radiation Related Adverse Events ………………………………………………..18 
 
10.3 
Chemotherapy Related Adverse Events ………………………………………….18 
 
11. 
SERIOUS ADVERSE EVENTS (SAE) AND REPORTING …..…………………..18 
11.1 
Serious Adverse Event ………………………………………………………..….18 
11.2 
SAE Reporting Guidelines for Johns Hopkins Hospital ……………………....18 
 
12. DATA AND SAFETY REPORTING/REGULATORY CONSIDERATION………...19  
12.1 
Data Quality Monitoring ........................................................................................19 
12.2 
Data Safety Monitoring Plan……………………………………………………..19 
12.3 
Data Reporting ……………………………………………………………………20 
12.4 
CTEP Multicenter Guidelines …………………………………………………...20 
12.5 
Cooperative Research and Development Agreement (CRADA) Clinical Trials 
Agreement (CTA) …………………………………………………………..…….20 
 
REFERENCES ………………………………………………………………….………....…21 
 
APPENDICES 
 
APPENDIX A 
Performance Status Criteria ……………………………………………..………….....23 
 
APPENDIX B 
RTOG Acute Morbidity Scoring Criteria ……………………………………………..24 
 
APPENDIX C 
      RTOG Late Morbidity Scoring Criteria ………….………………………….…..……26 
 
APPENDIX D 
      Study Calendar……………………….. ……………………………………….…..…..27 

September 29, 2022 
 
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1. OBJECTIVES 
 
1.1 Safety Run In  
 
1.1.1 Primary Objective 
 
To select a safe and tolerated dose schedule (ie: number of consecutive twice daily 
fractions) of LDFRT + temozolomide based on hematologic toxicity at one month 
following initiation of therapy. 
 
1.1.2 Secondary Objectives 
 
To estimate the acute and late radiation-associated neurologic toxicity of salvage 
LDFRT + temozolomide. 
 
1.2 Phase II  
 
1.2.1 Primary Objective 
 
1.2.1.1 To estimate the one year overall survival in patients treated with    
                  LDFRT + temozolomide for recurrent HGG. 
 
 
1.2.2 Phase II Secondary Objectives 
 
 
1.2.2.1 To estimate the 6 month progression free survival in patients treated with 
LDFRT plus temozolomide for recurrent HGG.  
 
1.2.2.2 To estimate the rate of pseudoprogression in patients treated with LDFRT 
plus temozolomide for recurrent HGG 
 
1.2.2.3 To characterize the chronologic sequence of pseudoprogression in 
patients treated with LDFRT plus temozolomide for recurrent HGG. 
 
1.2.2.4 To estimate the hematologic toxicity of salvage LDFRT + temozolomide. 
 
1.2.2.5 To estimate the radiation-associated acute and long term neurologic 
toxicity of salvage LDFRT + temozolomide. 
 
 
2. BACKGROUND 
 
2.1  
Study Disease 
 
High grade glioma (HGG) is one of the most lethal forms of human cancer (1).  The 
standard of care at the time of initial diagnosis of HGG consists of surgical resection 
followed by adjuvant radiation therapy and temozolomide chemotherapy, based on 

September 29, 2022 
 
2
the results of a randomized controlled trial which demonstrated a significant 
improvement in overall survival with the addition of temozolomide to adjuvant 
radiation therapy alone (1).  Although this study was performed in patients with 
GBM, the results are widely applied to patients with anaplastic astrocytoma (AA) 
who are treated with the same paradigm.  Despite recent advances in the treatment of 
HGG, the diagnosis remains essentially incurable and the tumor will recur in the vast 
majority of patients.   
 
 Management of patients with recurrent HGG remains controversial.  Accepted 
treatment options include temozolomide alone, repeat radiation therapy with 
concurrent temozolomide, or a clinical trial.  The response rate to second line 
therapies is limited and when effective the durability of response is generally poor.  
Improvements in salvage therapeutic options for HGG are therefore critical.  
 
 
2.2    
LDFRT Rationale 
 
 Numerous studies have shown that the slope of the cell survival curve is greater at 
very low doses of radiation than at the higher doses of radiation which are 
conventionally employed in the clinic (2-8).  The mechanism behind this phenomenon 
known as hyper-radiation sensitivity appears to be two-fold.  First, low doses of 
radiation do not induce cellular repair mechanisms such as ATM and mismatch repair 
that are typically activated with clinically relevant doses of radiation (2,9,10).  
Second, very small fractions of radiation manage to induce pro-apoptotic pathways 
without inducing pro-survival cascades that are activated with higher doses (11,12).  
Studies have shown that hyper-radiation sensitivity persists following multiple 
fractions of radiation (13) and that the effect is greatest in cells in the G2/M phase.  
Experiments in glioma cell lines have suggested that the point of maximum radiation 
hypersensitivity occurs with fractions of approximately 0.4-0.5 Gy. 
 
In spite of these data, low dose fractionated radiation therapy (LDFRT) is not typically 
employed in the clinic because in order to use it as a primary modality, patients would 
need to be treated with multiple fractions of radiation per day for many months, and 
this is not feasible.  However, in vitro and in vivo studies have suggested that LDFRT 
may be used to potentiate full dose chemotherapy, decreasing the development of 
resistance found with standard doses of radiation and chemotherapy (11-14).  Recent 
data in U87 glioblastoma cells suggest that LDFRT may be used to sensitize cells to 
the effects of temozolomide. Specifically, Gupta et al. (15) demonstrated that the slope 
of the cell survival curve is greater following treatment with temozolomide plus 
LDFRT (0.5 Gy x 4 fractions, 8 hours apart) compared with temozolomide plus 2 Gy 
of radiation. The mechanism behind this effect remains to be elucidated. 
 
 The concept of low dose fractionated radiation therapy as a chemotherapy-sensitizer 
has been previously evaluated in humans in the context of early phase clinical trials in 
other disease sites, and the results have been optimistic.  Arnold et al. (16) performed 
a phase II trial in patients with stage III and IV squamous cell carcinoma of the head 
and neck in which they used 0.8 Gy fractions of radiation twice daily to sensitize 
patients to induction chemotherapy with carboplatin and taxol.  They enrolled forty 

September 29, 2022 
 
3
patients and report an overall response rate of 82% (13% complete response, 69% 
partial response), which is better than otherwise expected.  In addition, they performed 
a second phase II trial in the same patient population using 0.5 Gy fractions of 
radiation twice daily to sensitize cells to carboplatin and taxol, and again report a 
favorable overall response rate of 88% (38% complete response, 50% partial 
response) (16).  The authors propose further evaluation of the regimen in a 
randomized controlled trial. 
 
Similarly positive results using LDFRT for chemotherapy sensitization were reported 
by Regine et al. (17) who performed a phase I/II trial of LDFRT plus gemcitabine in 
patients with unresectable or metastatic gastrointestinal tumors.  The median overall 
survival time was 10 months, which is better than historical data might predict for 
these aggressive tumors.   
 
A recent phase 2 trial evaluated ultrafractionated radiation therapy (3 daily doses of 
0.75 Gy to a total dose of 67.5 Gy) without temozolomide in patients with newly 
diagnosed unresectable GBM (Beauchesne 2010).  The results of this study were 
optimistic with no grade III or IV CNS toxicity, and PFS and OS which were superior 
to conventional RT alone based on historical controls.  
 
Given the promising preclinical and clinical data, the purpose of this trial is to 
examine the safety and efficacy of LDFRT as a chemo-potentiator of temozolomide in 
patients with recurrent HGG.   
 
2.2  
Temozolomide 
 
Temozolomide is a chemotherapeutic agent which is a standard component of 
treatment of patients with both newly diagnosed and recurrent HGG.  The drug is an 
orally administered 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 (18).  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 HGG 
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 
Amendment February 2017: 
 
The hypothesis of this study is low dose radiation hypersensitivity wherein very low 
doses of radiation in the range of 0.3-0.8 Gy actually demonstrate greater cell kill than 
more traditional radiation doses in the range of 1.8-3 Gy, seemingly because pro-

September 29, 2022 
 
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apoptotic pathways are activated while damage repair pathways are not (2-8).   
 
To date, a total of 22 patients have been enrolled.  Unexpectedly, the majority of 
patients have experienced substantial increases in contrast enhancement and edema as 
a result of treatment, which have then stabilized for many months.  Figure 1 shows an 
example patient.  Note the increase in contrast enhancement and edema at 3 months 
which then stabilizes and is markedly improved at month 11.  
 
 
Figure 1: T1 post-gadolinium MRI images at baseline, 3 months and 11 months 
following initiation of management accordingly to J11120. 
 
 
The phase 1 component of the study is completed and all patients are being treated 
according to cohort 1. In general patients have tolerated treatment well with 5 patients 
with SAEs attributable to the study treatment (fatigue in 2 patients, and 
lymphocytopenia, aphasia, cognitive disturbance each in 1 patient).  Two of 22 
patients had pathologically confirmed radionecrosis.  
 
This unanticipated pseudo-progression type response renders our original primary 
objective of response rate inappropriate.  With this amendment we wish to change the 
primary objective to one year overall survival and enroll the remaining nine patients.  
The current one year OS is 45.1% (80% CI: 28.2%, 60.9%), the median OS is 9.5 
months (median follow-up of 12.7 months) and the median PFS is 4.0 months.  Given 
that patients on this trial have been treated without any severe toxicities, it would be 
informative to determine if it is possible that there may be a delayed treatment effect 
that would indicate further study was warranted.  Since overall survival is the most 
definitive endpoint for a clinical trial, we would like to estimate this outcome with the 
full sample size of 31 and potentially use this information as a reference in a future 

September 29, 2022 
 
5
clinical trial.    
 
 
3. PATIENT SELECTION 
 
3.1  
Eligibility Criteria  
 
3.1.1 
Patients must have recurrent GBM or anaplastic astrocytoma. 
 
3.1.2 
The diagnosis of GBM or anaplastic astrocytoma must be histologically 
confirmed.  
 
3.1.3 
Patients must have been previously treated with surgical resection (any extent 
okay)  and radiation therapy plus temozolomide 
 
      3.1.4    Patients must be at least 12 months from completion of radiation therapy (to be  
                  consistent with the “rechallenge” group from Perry et al. JCO 2010 where the  
                  median time from completion of adjuvant radiation therapy to the time of  
                  progression was 19.69 months). 
 
 3.1.5    At least 2 months from completion of temozolomide (to be  
             consistent with the the “rechallenge” group from Perry et al. JCO 2010) 
 
3.1.6    Because no data regarding the effects of LDRT in patients <18 years of age, 
children are excluded from this study but will be eligible for future pediatric 
trials. 18 years. 
 
3.1.7 
ECOG performance status <2 (Karnofsky >60%, see appendix A). 
 
3.1.8 
There must be measurable disease on MRI. 
 
3.1.9 
Patients must have normal organ and marrow function as defined below: 
 
- leukocytes 
>3,000/mcL 
- absolute neutrophil count 
>1,500/mcL 
- platelets 
>100,000/mcL 
- total bilirubin 
within normal institutional limits 
- AST(SGOT)/ALT(SGPT) 
<2.5 X institutional upper limit of normal 
- creatinine 
within normal institutional limits 
 
OR 
- creatinine clearance 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal. 
 
3.1.10 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 

September 29, 2022 
 
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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. 
 
3.1.11 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.1.12 Temozolomide re-treatment is planned by the treating neuro-oncologist. 
 
3.1.12 The most recent brain tumor pathology obtained for the patient must be 
glioblastoma or anaplastic astrocytoma. 
 
 

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3.2  
Exclusion Criteria 
 
3.2.1 
Patients who are unable to receive MRIs will be excluded from the study since 
MRIs will be critical in monitoring the efficacy of therapy. 
 
3.2.2 
Patients may not be receiving any other investigational cancer treatment 
agents at the time of enrollment. 
 
3.2.3 
Patients may not have previously failed treatment with salvage temozolomide. 
 
3.2.4 
Patients may not have previously failed treatment with a VEGF inhibitor. 
 
3.2.5 Patients may not have previously been treated with >1 course of radiotherapy 
to the brain. 
 
3.2.6 
Patients may not have previously been treated with radiosurgery to the brain. 
 
3.2.7 
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. 
 
 
 
 
3.2.8    Pregnant and/or breastfeeding women are excluded. Women of child-bearing  
 
 
 
            potential who are unwilling or unable to use and acceptable method of birth   
                              control to avoid pregnancy for the entire study period and up to 12 weeks after  
      the study are excluded.  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 
 
Eligible patients will be entered on study centrally at the Johns Hopkins Hospital by the 
Study Coordinator. 
To register a patient, the following documents should be completed by the research nurse or 
 
data manager and sent to the Coordinating Center Study Coordinator via fax or email.  
 Copy 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. 
 

September 29, 2022 
 
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5. TREATMENT PLAN 
 
5.1   
Temozolomide 
 
All patients will receive temozolomide (150 to 200 mg per square meter for 5 days 
during each 28 day cycle) for a total of 1 year or until the time of disease progression.   
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.  Risks of 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. 
 
5.1.1 Therapy Modifications 
Delay, reduction, or discontinuation of temozolomide administration will be decided 
according to hematological and non-hematological adverse events (AE), as specified 
below. If the administration of temozolomide has to be interrupted, radiotherapy will 
be delayed, as well. Missed doses of temozolomide will not be made up after the end 
of radiotherapy. Blood work will be checked weekly, based on the discretion of the 
treating Medical Oncologist. 
 
If radiotherapy has to be temporarily interrupted for technical or medical reasons, 
unrelated to the temozolomide administration, then treatment with temozolomide may 
continue. 
 
5.2  
Low Dose Fractionated Radiation Therapy (LDFRT) 
 
All patients will receive 0.5 Gy of radiation therapy twice daily (at least 6 hrs. apart).  
This study will include a safety run-in component.  If > 33% of patients in the initial 
cohort of 6 experience grade 3 or greater hematologic toxicity (attribution of possible 
or above) according to the NCI Common Toxicity Criteria version 4, then a dose 
reduction will occur following the schedule listed below.  Otherwise, following a 1 
month waiting period after the first cycle of adjuvant LDFRT plus temozolomide for 
the first cohort of patients, the phase 2 study will open for full accrual. Patients will 
receive radiation with the first six 28-day cycles of temozolomide.   
 
 
Safety Run-in Dose Reduction Schedule 
 
Cohorts 
 
Radiation Schedule  
 
Cohort 1 
0.5 Gy bid on days 1-5 of temozolomide 
 
Cohort 2 
0.5 Gy bid on days 1-4 of temozolomide 
 
Cohort 3 
0.5 Gy bid on days 1-3 of temozolomide 
 
Cohort 4 
0.5 Gy bid on days 1 & 2 of temozolomide 

September 29, 2022 
 
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6 patients will be enrolled in the initial cohort.  Dose reduction will occur if 
>2 patients experience dose limiting toxicity. 
 
5.2.1 Definition of Dose-Limiting Toxicity 
Toxicity will be recorded according to the NCI Common Toxicity version 4.  Dose 
limiting toxicity will be considered grade 3 or greater hematologic toxicity 
(attribution of possible or above) according to this scale.  The criteria are available 
online at the Cancer Therapy Evaluation Program website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_4
0 
 
5.2.2.1.Radiation Treatment Planning 
 
5.2.2.1  Simulation 
 
 
All patients will undergo CT simulation preferably with intravenous contrast.  In 
addition they will undergo MRI simulation with T1 with gadolinium sequence.  
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 co-registered with the T1 post-gadolinium MRI.   
 
5.2.2.2 Target Delineation 
 
The gross tumor volume (GTV) will be contoured using the simulation CT 
scan and fused T1 with gadolinium sequence MRI.  The clinical tumor volume 
(CTV) will include the GTV plus approximately 0.5-1.5 cm margin.  The 
planning tumor volume (PTV) will include the CTV plus approximately 0.5 
cm margin.   
 
5.2.2.3 Normal Tissues 
 
Organs at risk including the eyes, lens, optic nerves, optic chiasm, brainstem, 
and spinal cord will be contoured on the planning CT scan.  Dose to adjacent 
structures will be limited as much as possible and dose will be recorded.  All 
patients will have been previously irradiated, however the maximum dose 
delivered in this protocol will be 30 Gy in 0.5 Gy fractions which is below the 
radiation tolerance typically allowed in patients undergoing repeat irradiation 
for HGG.   
 
   5.2.2.4  Equipment 
 
Patients will be treated using a megavoltage linear accelerator with nominal 
beam energy of 6 MV. 
 
5.2.2.5  Beam Verification 

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10 
 
Either daily on-line cone beam CT guidance or weekly portal imaging will be 
used for precise patient setup. 
 
 
 
5.2.3 Therapy Modifications 
 
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 
additional radiation or chemotherapy treatment will then be at the discretion of 
the treating medical oncologist and radiation oncologist.  
 
Treatment may be postponed for re-evaluation of disease. Participants may 
require further biopsies to confirm disease status. If results reveal stable 
disease, participants will continue protocol intervention. 
 
 
5.2.4 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 Therapy 
 
In the absence of treatment delays due to adverse events, LDFRT will be administered 
with the first 6 cycles of temozolomide and temozolomide will continue for a total of 
1 year and or until one of the following criteria applies: 
 
 Disease progression, 
 
 Intercurrent illness that prevents further administration of treatment, 
 
 Unacceptable adverse event(s), 
 
 Patient decides to withdraw from the study, or 
 
 General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 

September 29, 2022 
 
11 
 
      5.4          Duration of Follow Up 
 
Patients will be followed until the time of death or until circumstances prevent the 
patient from presenting for additional follow-up.  
 
5.5 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.3 
applies.  The reason for study removal and the date the patient was removed must be 
documented in the Case Report Form. Patients will continue to be followed for overall 
survival. Data from medical oncology, including MRI reports and additional 
chemotherapy, will be collected until time of death. 
 
6. CORRELATIVE/SPECIAL STUDIES 
Not applicable. 
 
7. STUDY CALENDAR 
See Appendix D.  Baseline evaluations and imaging are to be conducted within 4 weeks prior 
to start of protocol therapy.  Every effort should be made to adhere to the protocol timeline as 
closely as possible, but if studies are delayed or missed as a result of unavoidable conflicts 
such as hospitalization at an outside facility, deteriorating of patient status, or other adversity 
precluding presentation for evaluation, it will not be considered a protocol deviation.  
Toxicity assessments that cannot be done in person will be completed over the phone.  
 
In order to minimize the need for research-only in-person visits, telemedicine visits may be 
substituted for in person clinical trial visits or portions of clinical trial visits where determined 
to be appropriate and where determined by the investigator not to increase the participants 
risks. Prior to initiating telemedicine for study visits the study team will explain to the 
participant, what a telemedicine visit entails and confirm that the study participant is in 
agreement and able to proceed with this method. Telemedicine acknowledgement will be 
obtained in accordance with the Guidance for Use of Telemedicine in Research. In the event 
telemedicine is not deemed feasible, the study visit will proceed as an in-person visit. 
Telemedicine visits will be conducted using HIPAA compliant method approved by the 
Health System and within licensing restrictions. 
 
8. MEASUREMENT OF EFFECT 
 
Patients with measurable disease will be assessed by standard criteria.  For the purposes of 
this study, patients should be re-evaluated approximately every 8 weeks.   
 
8.1 Antitumor Effect 
 
Response and progression will be evaluated in this study using the international 
criteria proposed by the Response Assessment in Neuro-Oncology Working Group 
(RANO) (19).  
 

September 29, 2022 
 
12 
8.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with LDFRT. 
 
Evaluable for objective response.  Only those patients who have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
8.1.2  
8.1.3 Methods for Evaluation of Disease 
 
All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to 
evaluate patients at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used 
to assess the antitumor effect of a treatment. 
 
MRI:  T1 with gadolinium, T2 and FLAIR sequence MRI techniques should be 
performed with cuts of 5 mm or less in slice thickness contiguously.   
 
Corticosteroid use: Dosages of corticosteroids will be recorded at baseline as well 
as follow-up visits and will be incorporated into the response criteria.   
 
Clinical examination: Neurologic deficits and symptoms will be recorded at 
baseline as well as follow-up visits and will be incorporated into the response 
criteria.   
 
  
 
8.1.4 Progression-Free Survival  
 
Progression free survival will be measured from the date of initiation of salvage 
treatment to the date of documented progressive disease according to the RANO 
criteria (19).  
 
8.1.5 Overall Survival (OS) 
 
OS is defined as the duration of time from start of treatment to time of death from 
any cause. 
 
 
 
8.1.6 Pseudo-progression 
 

September 29, 2022 
 
13 
Pseudo-progression will be defined and MRI changes including T1 post-
gadolinium, T2 or T2 variants such as FLAIR imaging, with or without clinical 
deterioration and/or increase in dexamethasone dose which stabilizes or reverses 
on later evaluations without a change in oncologic intervention. 
 
8.1.7 Toxicity 
 
Toxicity will be monitored according to the criteria outlined in section 5.2.1. 
 
9. STATISTICAL CONSIDERATIONS 
 
9.1   Study Design/Endpoints 
 
 
 
 
 
9.1.1  Study Design 
 
This is a nonrandomized, open label, single institution phase II trial with a 
safety run-in to evaluate the safety and efficacy of LDFRT plus temozolomide 
in patients with recurrent HGG previously treated with surgical resection 
followed by adjuvant radiation therapy plus temozolomide.   
 
The original primary objective of this study was response rate where a CR+PR 
rate below 10% was considered clinically insignificant whereas a CR+PR rate 
above 25% was considered clinically significant using the temozolomide re-
challenge group B3 of the Perry et al. JCO 2010 study as a comparator.  
Response rate was considered an appropriate primary objective since this was 
considered a predominantly chemotherapy based trial.  We did not anticipate 
radiation-induced MRI changes (pseudo-progression) given the very low doses 
of radiation that are prescribed in this clinical trial. 
 
As of 2/10/2017, 22 patients had been treated on study.  At the time of the 
interim analysis, there were no clinical responses.  Given the unexpected 
number of patients experiencing pseudo-progression on this study, and the 
possible implications of this for assessing response rate or progression free 
survival (PFS), the primary objective of this study is being changed to one year 
overall survival (OS). The current one year OS is 45.1% (80% CI: 28.2%, 
60.9%).  The median OS at this time is 9.5 months with a median follow-up of 
12.7 months.  When stratifying by tumor type there is no statistically 
significant difference in outcomes by group.  The 17 patients with 
glioblastoma have a 1 year overall survival of 33% (80% CI: 13%-79%) and 
the 1 year overall survival for the 5 patients with anaplastic astrocytoma is 
60% (80% CI: 13%-79%).  These data suggest that early termination of the 
study due to futility is not warranted and support the revision of the primary 
endpoint to allow completion of the study with the originally intended sample 
size. 
 
 
9.1.2 Endpoints 

September 29, 2022 
 
14 
 
9.1.2.1 Safety Run-In 
 
 
9.1.2.1.1  Primary Endpoint 
 
Dose-limiting toxicity (DLT) is defined as hematologic toxicity 
during the month following cycle #1 of temozolomide plus LDFRT  
grade ≥3 by NCI common toxicity criteria version 4.  All patients 
who receive any amount of LDFRT will be evaluable for toxicity. 
The recommended phase II dose will be the highest dose yields ≤ 
33% DLT rate. 
 
 
 
 
 
 
 
9.1.2.1.2  Secondary Endpoint 
 
Radiation-associated neurologic toxicity of LDFRT plus 
temozolomide using the RTOG/EORTC acute (≤3 months) and late 
(>3 months) radiation morbidity scoring criteria at 3, 6 and 12 
months following completion of therapy.  Since the total radiation 
dose to the brain is low and delivered in very small fractions, the 
likelihood of radiation associated toxicity is expected to be low.  
The radiation-induced necrosis rate is less than 5% in patients with 
recurrent gliomas re-irradiated to a median dose of 36 Gy using 
conventional 2 Gy fractions (Combs JCO 2005).  However, we will 
be collecting late radiation toxicity data and if there are four 
patients with radiation related symptomatic necrosis believed to be 
a result of the LDFRT, the trial will be suspended to accrual and a 
safety review by the institutional DSMB will be requested.  
 
 
9.1.2.1 Phase II 
Amended Primary Objective: Estimate one year OS in 
patients treated with LDFRT + temozolomide for recurrent 
GBM.  
 
9.1.2.1.1 Primary Endpoint: OS will be measured from initial salvage 
starting date to the date of death. 
 
 
9.1.2.1.2   Secondary Endpoints: 
 
          9.1.2.1.1.1.1  PFS-6: The definition of progression will be 
based on RANO criteria (19).  Progression free will be measured from 
initial salvage starting date to the date of progressive disease is defined 
(documented).   
 
9.1.2.1.1.1.1 
Occurrence of pseudoprogression at any time point 
will be recorded as a binary variable for each patient 
(yes/no) 

September 29, 2022 
 
15 
 
9.1.2.1.1.1.2   
 
 
 
 
      
Use NCI common toxicity criteria (version 4, see 
section 5.2.1) to record the toxicity of LDFRT 
plus temozolomide for each patient associated 
with the treatment.  All patients who receive any 
amount of LDFRT will be evaluable for toxicity. 
 
 
 
 
 
 
 
 
 
1.2.1.1.1.3 Use the RTOG/EORTC acute and late radiation 
morbidity scoring criteria (see appendix B and C) to 
record the toxicity of LDFRT plus temozolomide for 
each patient with recurrent HGG.  All patients who 
receive any amount of LDFRT will be evaluable for 
toxicity. 
 
9.1 
Sample Size/Accrual Rate 
 
9.2.1 Sample Size 
 
 
9.2.1.1 Safety run-in 
 
A minimum of 6 and up to 24 patients will be enrolled for the safety run-
in study at an accrual rate of 1 patients per month at the starting dose 0.5 
Gy twice daily on days 1-5 of temozolomide. The exact number of 
patients will depend on the number of dose levels in this phase.  
 
 
 
  
 
 
 
    9.2.1.2 Phase II 
 
Amended Primary Objective:  The amended primary objective of the 
study is one year OS.  The current one year OS after 22 patients have 
been enrolled and followed for a median of 12.7 months is 41.5% (80% 
CI: 25%, 68%).  The one year OS for the historical reference used for 
this study, TMZ alone (Perry JCO 2010), was reported as 28.6%.  
Claiming improvement in one year OS within the context of a protocol 
with an amended primary objective would not be justified, however, the 
lower bound of the current 80% confidence interval is fairly promising 
compared to the historical estimate.  Additional follow-up of the current 
patients and completing enrollment to the sample size of 31 will allow us 
to estimate one year OS with greater precision: width of current CI 0.33 
versus simulated mean width of 0.23, Table 1.  A one year OS with a 
lower bound of an 80% CI greater than 28% would be considered 
sufficiently promising for further study.     
 
Table 1.  Lower bound and mean width of 80% CI for one year OS based on 500 
simulations with a sample size of 31  
 

September 29, 2022 
 
16 
Simulated true 
12 mo. OS 
Simulations with lower 
bound > 28.6% 
Mean width of 80% CI: 
0.30 
19.8% 
0.21 
0.35 
38.6% 
0.22 
0.40 
59.0% 
0.22 
0.47 
82.8% 
0.23 
0.50 
93.4% 
0.23 
0.55 
98.0% 
0.23 
 
 
Original Primary Objective: The primary objective of this trial is to 
evaluate the therapeutic efficacy of LDFRT plus temozolomide in patients 
with recurrent HGG.  A true (partial or complete) response rate below 10% 
is considered clinically insignificant and a true (partial or complete) 
response rate above 25% clinically is considered clinically significant. A 2-
stage design will be used to follow for early termination if there is strong 
early evidence to support the null hypothesis that the true response rate is 
at most 10%. The alternative hypothesis is that the true response rate is at 
least 25%.  A total of 31 patients will yield 80% power to detect a response 
rate (PR+CR) of 25% compared to a 10% rate among patients treated by 
TMZ alone (Perry JCO 2010) at a one-side alpha level of 0.1. Note that in 
this study (Perry JCO 2010) the outcomes for the “rechallenge” GBM 
group was comparable to the AA group. 
  
 
 
 
 
       
In the first stage, if 2 or fewer patients of the first 20 accrued to the study  
show response (PR+CR), the study will be terminated. Otherwise, the 
study will continue to a second stage with additional 11 patients to a total 
of 31 patients. If 6 or more out of the 31 patients had PR or CR, the 
LDFRT plus temozolomide will be considered efficacious and 
recommended for future comparative study.  The estimated probability of 
early stopping for null is 68%. The probability of early stopping under the 
alternative hypothesis is 9%.  The 6 patients from the selected phase II 
dose enrolled in the safety run-in will count towards the phase II trial, so 
that the minimum number of patient for the study is 31 and the maximum 
is 49.  
 
Safety Monitoring:  
 
Early stopping for toxicity:  according to observed severe adverse event 
(about 5% necrosis rate) that related to RT from the study with higher RT 
dose than this study among re-radiation HGG patients (Combs JCO 2005), 
it is very unlikely this low RT dose study will yield DLTs or later RT 
toxicity as necrosis. However, the study will monitor SAEs (RT related 
DLTs or Necrosis) continuously through the trial. Assuming the low dose 
RT related SAE rate follows a binomial distribution.  In general, the trial 
enrollment will be suspend for safety consultation if a posterior probability 
of SAE rate exceeding 0.2 is great than 60%.  The prior for this monitoring 
rule is a Beta distribution assuming a mean SAE rate of 5%.  

September 29, 2022 
 
17 
The safety stopping rule and the operating characteristics are shown below 
and there are based on 5000 simulations:  
 
SAE event in 2 out of 3 patients.  Pr(Risk>0.2| Data) = 0.6 
SAE event in 3 out of 6 patients.  Pr(Risk>0.2| Data) = 0.7 
SAE event in 4 out of 9 patients.  Pr(Risk>0.2| Data) = 0.76 
SAE event in 4 out of 12 patients.  Pr(Risk>0.2| Data) = 0.62 
SAE event in 5 out of 15 patients.  Pr(Risk>0.2| Data) = 0.69 
SAE event in 6 out of 18 patients.  Pr(Risk>0.2| Data) = 0.74 
SAE event in 6 out of 21 patients.  Pr(Risk>0.2| Data) = 0.63 
SAE event in 7 out of 24 patients.  Pr(Risk>0.2| Data) = 0.69 
SAE event in 8 out of 27 patients.  Pr(Risk>0.2| Data) = 0.74 
SAE event in 8 out of 30 patients.  Pr(Risk>0.2| Data) = 0.65 
SAE event in 9 out of 35 patients.  Pr(Risk>0.2| Data) = 0.64 
SAE event in 10 out of 40 patients.  Pr(Risk>0.2| Data) = 0.63 
SAE event in 11 out of 45 patients.  Pr(Risk>0.2| Data) = 0.62 
SAE event in 13 out of 55 patients.  Pr(Risk>0.2| Data) = 0.61 
 
Operating characteristics: 
Underline true SAE rate  Probability declare  unsafe  Average sample size 
0.10 
3.3 
160 
0.15 
18.4 
140 
0.20 
60.5 
91 
0.30 
99.7 
24 
0.35 
100 
17 
 
All SAEs or toxicity events will be tabulated by type and grade based on 
NCI CTC Version 4.0 for toxicity and adverse events.  SAEs with an 
attribution of possible or above will be evaluated for early stopping. 
Proportion of individual type of SAE event will be estimated using the 
binomial distribution along with 95% confidence interval (exact method).  
 
9.2.1.3  Accrual 
 
    We anticipate enrollment of approximately 1-2 patients per month to the    
     protocol with accrual completed in approximately 3-4 years.   
 
        9.2.1.4   Stratification Factors 
 
 
 
 
 
    There will be no stratification factors upon initial enrollment in the protocol.   
 
9.3    Statistical Methods of Analysis 
 
9.3.1    Safety/Toxicity:  NCI CTC version 4.0 will be used for scoring the toxicity and  
  
    adverse events.   The severity and frequency of the toxicity will be tabulated by  
  
    the tested dose or doses using descriptive statistics. The proportions of patient  
  
    who experienced grade 3 or above toxicities will be estimated, along with 95%  

September 29, 2022 
 
18 
           confidence intervals by each type of toxicity. 
 
9.3.2  Pseudo-progression: The proportion of patients who had pseudo-progression 
will be reported with 95% confidence intervals. 
 
9.3.2  PFS-6: The definition of progression will be based on RANO criteria (19).  
          Progression free will be measured from initial salvage starting date to the date of  
          progressive disease is defined (documented). The proportion of PFS-6 will be  
          estimated along with 95% confidence intervals using the exact binomial method. 
 
9.3.3 OS: the survival time is defined from the date of treatment start to the date of death.  
           Patients who have not died by the analysis data cut-off date will be censored at their last  
date known to be alive. The Kaplan-Meier method will be used to estimate one        
year survival, and median survival along with 80% confidence intervals. 
 
9.3.4  Radiation Toxicity: descriptive statistics will be used to summarize radiation  
          toxicity based on the RTOG/EORTC acute and late radiation morbidity scoring  
          criteria (see appendix B and C) for all patients who had any radiation treatment  
          in this study.    
 
10.   ADVERSE EVENTS AND RECORDING  
 
10.1 
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. 
 
10.2      Radiation Related Adverse Events  
 
All radiation related adverse events will be recorded on the local toxicity case report 
forms. 
 
      10.3 
Chemotherapy Related Adverse Events 
 
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.   
 
11. SERIOUS ADVERSE EVENTS (SAE) AND REPORTING 
 
11.1    Serious Adverse Event 

September 29, 2022 
 
19 
11.1.1 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. 
 
11.2      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.   
 
12.    DATA AND SAFETY REPORTING/ REGULATORY CONSIDERATIONS 
 
 
12.1  Data Quality Monitoring 
 
The SKCCC Compliance Monitoring Program will provide external monitoring for 
JHU affiliated sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019). 
The SMC Subcommittee will determine the level of patient safety risk and 
level/frequency of monitoring 

September 29, 2022 
 
20 
 
 
12.2   Data Safety Monitoring Plan 
 
The SKCCC Compliance Monitoring Program will provide external monitoring for 
JHU affiliated sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019). 
The SMC Subcommittee will determine the level of patient safety risk and 
level/frequency of monitoring 
 
12.3 
Data Reporting 
 
12.3.1 
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. 
 
12.3.2      Responsibility for Submissions 
 
Not applicable. 
 
12.4 
CTEP Multicenter Guidelines 
 
Not applicable. 
 
12.5 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA) 
 
Not applicable 
 
 
 
 
 
 
 
 
 
 

September 29, 2022 
 
21 
REFERENCES 
 
1. Stupp R, Mason WP, van den Bent MJ, et al.  Radiotherapy plus concomitant and 
adjuvant temozolomide for glioblastoma.  N Engl J Med 2005;352:987-96. 
2.  Joiner MC, Marples B, Lambin P, et al.  Low dose hypersensitivity: current status and 
possible mechanisms.  Int J Radiat Oncol Biol Phys 2001;49(2):379-389. 
3. Marples B, Lambin P, Skov KA, Joiner MC.  Low dose hyper-radiosensitivity and 
increased radioresistance in mammalian cells.  Int J Radiat Biol 1997;71(6):721-35. 
4. Lambin P, Marples B, Fertil B, Malaise EP, Joiner MC.  Hypersenstivity of a tumour cell 
line to very low doses of radiation.  Int J Radiat Biol 1993;63(5):639-50. 
5. Singh E, Arrand JE, Joiner MC.  Hypersensitive response of normal lung epithelial cells 
at low radiation doses.  Int J Radiat Oncol Biol Phys 1994;65(4):457-64. 
6. Skarsgard LD, Skwarchuck MW, Wouters BG, Durand RE.  Substructure in radiation 
response at low dose in cells of human tumor cell lines.  Radiat Research 
1996;146(4):388-98. 
7. Wouters BG, Skarsgard LD.  The response of human tumor cell lines to low radiation 
doses: Evidence of enhanced sensitivity.  Rad Research 1994;138:S76-S80.  
8. Short S, Mayes C, Woodcock M, Johns H, Joiner MC.  Low dose hypersensitivity in the 
T98G human glioblastoma cell line.  Int J Radiat Oncol Biol Phys 1999;75(7):847-55. 
9. Bakkenist CJ, Kastan MB.  DNA damage activates ATM through intermolecular 
phosphorylation and dimer dissociation.  Nature 2003;421(6922):499-506. 
10. Krueger SA, Collis SJ, Joiner MC, Wilson GD, Marples B.  Transition in survival from 
low-dose hyper-radiosensitivity to increased radioresistance is independent of activation 
of ATM Ser1981 activity.  Int J Radiat Oncol Biol Phys 2007;69(4):1262-71. 
11. Chendil D, Oakes R, Alcock R, et al. Low dose fractionated radiation enhances the 
radiosensitization effect of paclitaxel in colorectal tumor cells with mutant p53.  Cancer 
2000;89(9):1893-1900.  
12. Dey S, Spring PM, Arnold S, et al.  Low dose fractionated radiation potentiates the effects 
of paclitaxel in wild type and mutant p53 head and neck tumor cell lines.  Clinical Cancer 
Research 2003;9:1557-65. 
13. Short SC, Kelly J, Mayes CR, et al.  Low-dose hypersensitivity after fractionated low 
dose irradiation in vitro.  Int J Radiat Biol 2001;77(6):655-664. 
14. Spring PM, Arnold SM, Shajahan S, Brown B, Dey S, et al. Low dose fractionated 
radiation potentiates the effects of taxotere in nude mice xenografts of squamous cell 
carcinoma of head and neck.  Cell Cycle 2004;3(4):479-85. 
15. Gupta S, Nagpal N, Ahmed M.  Low dose fractionated radiation as a potentiator of 
temozolomide in brain cancer cell lines.  Radiation Research Society 2010. 
16. Arnold SM, Regine WF, Ahmed M, et al.  Low dose fractionated radiation as a 
chemopotentiator of neoadjuvant paclitaxel and carboplatin for locally advanced 
squamous cell carcinoma of the head and neck: results of a new treatment paradigm.  Int J 
Radiat Oncol Biol Phys 2004;58(5):1411-17. 
17. Regine WF, Hanna N, Garofalo MC, Doyle A, et al.  Low dose radiotherapy as a 
chemopotentiator of gemcitabine in tumors of the pancreas or small bowel: a phase I 
study exploring a new treatment paradigm.  Int J Radiat Oncol Biol Phys 2007;68(1):172-
7. 
18. Hegi ME, Diserens AC, Gorlia T, et al.  MGMT gene silencing and benefit from 
temozolomide in glioblastoma.  N Engl J Med 2005;352:997-1003. 

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19. Wen PY, Macdonald DR, Reardon D, et al.  Updated response assessment criteria for high 
grade gliomas: response assessment in neuro-oncology working group.  J Clin Oncol 
2010;28(11):1963-1972. 
20. Perry JR, Bellanger K, Mason WP, et al.  Phase II trial of continuous dose intense 
temozolomide in recurrent malignant glioma: RESCUE study.  J Clin Oncol 
2010;28(12):2051-7.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

September 29, 2022 
 
23 
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. 
 
 
 
 
 
 
 
 
 
 

September 29, 2022 
 
24 
APPENDIX B: 
RTOG Acute Morbidity Scoring Criteria 
 
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 
injection, 
increased 
tearing 
Moderate 
conjunctivitis 
with or 
without 
keratitis 
requiring 
steroids 
and/or 
antibiotics, 
dry eye 
requiring 
artificial tears, 
iritis with 
photophobia 
Severe keratitis 
with corneal 
ulceration, 
objective 
decrease in 
visual acuity or 
in visual fields, 
acute 
glaucoma, 
panopthalmitis 
Loss of vision 
(unilateral or 
bilateral) 
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 
Neurologic 
findings 
requiring 
hospitalization 
for initial 
management 
Serious 
neurologic 
impairment 
which included 
paralysis, 
coma, or 
seizures, 
despite 
medications.  
Hospitalization 

September 29, 2022 
 
25 
steroids 
and/or anti-
seizure agents 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

September 29, 2022 
 
26 
APPENDIX C: 
RTOG Late Radiation Morbidity Scoring Criteria 
 
 
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 
Asymptomatic 
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 
 
 
 

September 29, 2022 
 
27 
APPENDIX D:  STUDY CALENDAR 
Cycles 1 – 6: Radiation and Temodar  
  
Pre-
Study1 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Wk 
14 
Wk 
15 
Wk 
16 
Wk 
17 
Wk 
18 
Wk 
19 
Wk 
20 
Wk 
21 
Wk 
22 
Wk 
23 
Wk 
24 
LDFRT2 
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
Temozolomide 
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
Informed 
consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history3 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
Physical exam 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vital signs 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Height  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Weight 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Performance 
status 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
CBC with diff4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NCI Common 
Toxicity Criteria 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
RTOG 
Acute/Late 
Morbidity 
Criteria5 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
MRI6 
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
  
  
  
 
  
  
  
X 
B-HCG 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
1 Baseline evaluations and imaging are to be conducted within 4 weeks prior to start of protocol therapy. 
2 Patients receive temozolomide (150 to 200 mg per square meter) and 0.5 Gy of radiation therapy twice daily (at least 6 hrs. apart) for 5 days during each 28 day cycle for a total of 6 cycles or until 
the time of disease progression.  Cycles 1 through 6 will always start on a Monday. 
3Medical history should be a complete history at pre-study evaluation, but later histories may be interval toxicity evaluations only.   

September 29, 2022 
 
27 
4Laboratory tests will be requested and performed at the discretion of the patient’s medical oncologist.  
5Use RTOG Acute Toxicity Criteria during RT and for first 6 months following completion of RT.  Use RTOG Late Toxicity Criteria at baseline and at scheduled intervals 6 months following completion 
of RT. 
6MRI imaging will be performed approximately every 2 months during temozolomide and then according to the schedule outlined above.  MRI sequences must include at a minimum T1 with 
gadolinium, T2 and FLAIR sequences.  Other sequences may be obtained at the provider’s discretion.  An MRI which is delayed or missed as a result of the deterioration of the patient’s clinical 
condition or other adversity will not be considered a protocol violation. 
 
Cycles 7 – 12: Temodar Only and Follow up  
 
Wk 
25 
Wk 
26 
Wk 
27 
Wk 
28 
Wk 
29 
Wk 
30 
Wk 
31 
Wk 
32 
Wk 
33 
Wk 
34 
Wk 
35 
Wk 
36 
Wk 
37 
Wk 
38 
Wk 
39 
Wk 
40 
Wk 
41 
Wk 
42 
Wk 
43 
Wk 
44 
Wk 
45 
Wk 
46 
Wk 
47 
Wk 
48 
 
6 
MFU 
12 
MFU6 
3 
MFU 
  
Temozolomide 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
  
  
Interval 
medical 
history 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
X 
Physical exam 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X4 
X4 
X4 
Performance 
status 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
X 
CBC with diff1 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
X 
CMP1 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
X 
NCI Common 
Toxicity 
Criteria 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
  
  
RTOG 
Acute/Late 
Morbidity 
Criteria2 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
X 
MRI3 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
X 
X 
X 
 
1Laboratory tests will be requested and performed at the discretion of the patient’s medical oncologist.  
2Use RTOG Acute Toxicity Criteria during RT and for first 6 months following completion of RT.  Use RTOG Late Toxicity Criteria at baseline and at scheduled intervals 6 months following completion 
of RT. 
3MRI imaging will be performed approximately every 2 months during temozolomide and then according to the schedule outlined above.  MRI sequences must include at a minimum T1 with 
gadolinium, T2 and FLAIR sequences.  Other sequences may be obtained at the provider’s discretion.  An MRI which is delayed or missed as a result of the deterioration of the patient’s clinical 
condition or other adversity will not be considered a protocol violation. 
4The physical exams at follow-up may be focused neurological examinations 
5Follow-Up appointments are permitted a +/- 10 day tolerance window 

September 29, 2022 
 
27 
6Continue patient follow-up with interval histories and MRI until the time of patient death.  After 12 months following completion of temozolomide, follow-up histories and imaging will be at the 
provider’s discretion.