Phase I Clinical Trial of GRID Therapy in Pediatric Osteosarcoma of the Extremity
Phase: NA
Conditions: Osteosarcoma in Children, Radiation Toxicity
Sponsor: University of Arkansas

Study Title: 
Principal Investigator: 
Biostatistician: 
Medical Monitor: 
Study location(s): 
Sponsor: 
Funding Source:  
Version Number:
NCT#: 
Version Date: 
Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the 
extremity 
Leslie Harrell, DO 
University of Arkansas for Medical Sciences 
Department of Radiation Oncology 
4301 W. Markham #724  
Little Rock, Arkansas 72205 
501-526-6591
lharrell@uams.edu
Eric R. Siegel, M.S. 
University of Arkansas for Medical Sciences 
Department of Biostatistics 
Dr. Rangaswamy Govindarajan 
University of Arkansas for Medical Sciences 
Division of Hematology/Oncology 
University of Arkansas for Medical Sciences 
University of Arkansas for Medical Sciences 
TBD 
7.0 
NCT03139318
November 9, 2020 

Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
IRB #205993 
PI: Leslie Harrell, DO 
Sponsor:  UAMS 
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Table of Contents 
1.0 
LIST OF ABBREVIATIONS .............................................................................................. 4 
2.0 
STUDY SCHEMA .......................................................................................................... 5 
3.0 
STUDY SUMMARY ....................................................................................................... 5 
4.0 
BACKGROUND AND RATIONALE .................................................................................. 6 
4.1 
Disease Background ..................................................................................................... 6 
5.0 
STUDY OBJECTIVES ...................................................................................................... 7 
5.1 
Primary Objectives....................................................................................................... 7 
5.2 
Secondary Objectives .................................................................................................. 7 
6.0 
STUDY POPULATION ................................................................................................... 7 
6.1 
Inclusion Criteria:......................................................................................................... 7 
6.2 
Exclusion Criteria ......................................................................................................... 8 
7.0 
INVESTIGATIONAL PLAN .............................................................................................. 8 
7.1 
Invesigational Plan ....................................................................................................... 8 
7.2 
Duration of Follow Up.................................................................................................. 8 
7.3 
Removal of Subject from Study .................................................................................... 8 
8.0 
STUDY PROCEDURES ................................................................................................... 8 
8.1 
Screening/Baseline Procedures .................................................................................... 8 
8.2 
Study Assessments: ..................................................................................................... 8 
8.3 
Removal of Subjects from Study .................................................................................. 9 
9.0 
MEASUREMENT OF EFFECT .......................................................................................... 9 
10.0 
ADVERSE EVENTS ...................................................................................................... 10 

Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
IRB #205993 
PI: Leslie Harrell, DO 
Sponsor:  UAMS 
 
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10.1 
Adverse Event Monitoring ......................................................................................... 10 
10.2 
Definitions ................................................................................................................. 11 
10.3 
Reporting Requirements for Adverse Events .............................................................. 12 
11.0 
STATISTICAL CONSIDERATIONS.................................................................................. 12 
11.1 
Study Design/Study Endpoints ................................................................................... 12 
11.2 
Evaluation Plan .......................................................................................................... 13 
11.3 
Sample Size Estimation.. ............................................................................................ 13 
12.0 
STUDY MANAGEMENT .............................................................................................. 14 
12.1 
Registration Procedures............................................................................................. 14 
12.2 
Data Management ..................................................................................................... 14 
12.3 
Monitoring and Auditing ............................................................................................ 14 
13.0 
REFERENCES ............................................................................................................. 16 
 

Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
IRB #205993 
PI: Leslie Harrell, DO 
Sponsor:  UAMS 
 
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1.0 
LIST OF ABBREVIATIONS 
 
AE 
 
 
 
Adverse Event 
C3PR 
 
 
 
Cancer Biomedical Informatics Grid 
CCTO 
 
 
 
Cancer Clinical Trials Office 
Co-PI 
 
 
 
Co-Investigator 
CRA 
 
 
 
Clinical Research Assistant 
CRF 
 
 
 
Case Report Form 
CTCAE  
 
 
Common Terminology Criteria for Adverse Events 
DLT 
 
 
 
Dose Limiting Toxicity 
FDA 
 
 
 
Federal Drug Administration 
Gy 
 
 
 
Gray 
GCP 
 
 
 
Good Clinical Practice 
GRID 
 
 
 
Spatially Fractionated Radiation Therapy 
IRB 
 
 
 
Institutional Review Board 
MTD 
 
 
 
Maximum Tolerated Dose 
NCI 
 
 
 
National Cancer Institute 
ORRA  
 
 
Office of Research Regulatory Affairs  
PI 
 
 
 
Principal Investigator 
SAE 
 
 
 
Serious Adverse Event 
SOP 
 
 
 
Standard Operating Procedure 
UAMS  
 
 
University of Arkansas for Medical Sciences 
 
 

Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
IRB #205993 
PI: Leslie Harrell, DO 
Sponsor:  UAMS 
 
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2.0 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
3.0 
STUDY SUMMARY 
 
Title 
Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity
 
Protocol Number 
205993 
Phase 
1 
Methodology 
Prospective, single-arm “3+3” dose-escalation design 
Study Duration 
12 months 
Study Center(s) 
Single center (UAMS) 
Objectives 
To evaluate the toxicity profile of GRID therapy using dose levels of 10Gy, 
15Gy and 20Gy in pediatric osteosarcoma of the extremity. 
Number of Subjects 
Treated 
A minimum of 6 and maximum of 12 subjects will be treated.  
Diagnosis and Main 
Inclusion Criteria 
Subjects, 5-21 years of age, with a diagnosis of non-metastatic extremity 
osteosarcoma who have been prescribed GRID radiotherapy by their 
treating physician 
 Primary Outcome 
Measures 
Dose-limiting toxicity (DLT), which is defined as a treatment-related AE of 
Grade 3 or higher, as assessed at either 30 days or 90 days following 
surgery. 
Statistical Methodology 
Rule-based evaluation of DLTs to determine the MTD of GRID 
 
 
 
 
Surgery 
GRID 
Chemotherapy 

Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
IRB #205993 
PI: Leslie Harrell, DO 
Sponsor:  UAMS 
 
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4.0 
BACKGROUND AND RATIONALE 
4.1 Disease Background 
Osteosarcoma response to preoperative chemotherapy is evaluated by histological examination 
of the resected tumor specimen. Patients who achieve a good histological response to pre-
operative chemotherapy, defined as < 10% viable tumor, experience considerably better survival 
than those who have a poor response (≥ 10% viable tumor). Five-year survival for good 
responders is in the region of 75-80%, compared to 45-55% for poor responders [1, 2]. The 
percentage of osteosarcoma patients who have good response to pre-operative chemotherapy 
has ranged in the past from 30% to 55% with recent reports clustering around 45% [1-3]. 
 
The likelihood of a patient having a good response to neo-adjuvant chemotherapy is not known 
until after completion of pre-operative chemotherapy and surgery. The majority of patients 
achieving a poor response to pre-operative chemotherapy will eventually relapse even with 
modification in chemotherapy in the adjuvant setting. Radiation therapy is reserved for 
scenarios wherein complete surgical resection cannot be achieved. Radiotherapy is also 
recommended for inoperable sites or those with inadequate margins at the time of surgery [15]. 
Since there is nearly a factor-of-2 difference in survival for good versus poor responders, 
strategies are needed to predict poor responders to pre-operative chemotherapy so that 
intensification of treatment can be offered to this group of patients early in their course of 
treatment. 
 
 
Radiation therapy can theoretically be used as intensification of therapy prior to surgery for 
patients with osteosarcoma. However, a 5-week course of conventional radiation therapy in the 
pre-operative setting may delay not only surgery but the initiation of adjuvant chemotherapy in 
a group of patients with potentially compromised survival. 
 
 
A feasible and more tractable possibility is the use of spatially fractionated radiation therapy 
(GRID) because it is a single-fraction treatment (with doses of 10Gy, 15Gy or 20Gy) that has 
been shown to have only minor side effects. 
 
Spatially fractionated radiotherapy (GRID) is a technique of irradiation that has been used 
successfully for the curative or palliative treatment of bulky tumors ≥ 6 cm [5-7]. Irradiation is 
delivered through a specially made grid collimator or by using a multi-leaf collimator (MLC) as a 
grid field shaper (5, 8-10). In GRID therapy the target volume does not receive a homogeneous 
dose of radiation. Only the volume under the open grid areas receives irradiation from the 
primary beam. Our results [11] have shown that GRID followed by definitive chemoradiation 
resulted in excellent control of bulky disease (79%) in patients with locally advanced squamous-
cell carcinoma of the head and neck. In these patients, acute toxicity profiles were acceptable 
and were similar to reports of chemotherapy and radiotherapy alone. In addition, no patient has 
developed a local recurrence in the irradiated GRID volume, but several have developed distant 
metastatic disease, which is common in this population. Our series also demonstrated that GRID 
is a feasible and valuable therapeutic option for bulky disease presentation. The therapeutic 
advantage of GRID therapy has been evaluated. Zwicker [12] et al reported that, for a wide 
range of tumor radiosensitivities, GRID therapy may have a significant therapeutic advantage 
over open-field radiotherapy to achieve the same level of tumor-cell kill. Highly radioresistant, 

Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
IRB #205993 
PI: Leslie Harrell, DO 
Sponsor:  UAMS 
 
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hypoxic cells are often present in bulky untreated tumors, and it is in these cases in which GRID 
use appears more advantageous.  
 
Based on the above clinical experience, we hypothesize that GRID can be used safely in pediatric 
patients with osteosarcoma of the extremity, and will show a favorable toxicity profile in this 
population. However, the toxicity profile of GRID therapy, at any dose level, in pediatric patients 
is unknown.  
 
Therefore, the purpose of this phase 1 clinical trial is to investigate the toxicity profile of GRID in 
pediatric osteosarcoma of the extremity. 
5.0 
STUDY OBJECTIVES 
5.1 Primary Objectives 
1)  Safety - To evaluate the toxicity profile of GRID therapy using dose levels of     
 
10Gy, 15Gy and 20Gy in pediatric osteosarcoma of the extremity. 
5.2 Secondary Objectives 
1) To determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose of 
GRID in patients with pediatric osteosarcoma of the extremity 
2) To histologically evaluate the extent of tumor necrosis after pre-operative chemotherapy 
combined with GRID therapy in pediatric osteosarcoma of the extremity patients. 
 
6.0 
STUDY POPULATION 
Research subjects will be recruited from the Radation Oncology clinic on the UAMS campus. The 
potiental research subject will be identified by the physician during their routine clinic visit. Prior 
to any research activities, the patient will be approached for participation in the study by their 
physician, who will discuss the protocol along with the risks and potential benefits of participating 
in it. A clear statement will be made concerning the voluntary nature of participation and that the 
decision will have no effect on their remaining care. 
We plan to consent up to 15 subjects in order to reach our maximum accrual of 12 subjects. 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria 
to be enrolled in the study. Study procedures may not begin until a subject is consented. 
6.1 Inclusion Criteria: 
1. History of cytological or histological documentation of non-metastatic extremity 
osteosarcoma 
2. 5 - 21 years of age 
3. Subject is eligible for, or has already received, routine chemotherapy for osteosarcoma 
4. Subject is eligible for routine surgery for the treatment of non-metastatic extremity 
osteosarcoma 
5. Informed consent is obtained 
 

Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
IRB #205993 
PI: Leslie Harrell, DO 
Sponsor:  UAMS 
 
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6.2 Exclusion Criteria 
1. Women with a positive urine pregnancy test are excluded from this study; women of 
childbearing potential (defined as those who have not undergone a hysterectomy) must 
agree to refrain from breast feeding and practice adequate contraception as specified in 
the informed consent. Adequate contraception consists of oral contraceptive, 
implantable contraceptives, injectable contraceptives, a double barrier method, or 
abstinence  
2. Unable to comply with study procedures 
 
7.0 
INVESTIGATIONAL PLAN 
7.1 Invesigational Plan 
Upon consenting to the study, the subject will attend their scheduled routine chemotherapy as 
prescribed by the treating Pediatric Oncologist (unless subject has already received 
chemotherapy). This will be followed by radiation treatment as discussed with the Radiation 
Oncologist.    
At 
their 
radiation 
treatment 
visits, 
the 
GRID 
procedure 
will 
be 
implemented.  Following the completion of the scheduled radiation treatment, the subject will 
proceed to routine surgery for osteosarcoma.  Post-surgical chemotherapy will be prescribed as 
per the treating Pediatric Oncologist. Following surgery, the subject will be seen in Radiation 
Oncology twice for follow-up visits related to their radiation treatment.   
7.2 Duration of Follow Up 
              Subject will not be followed once protocol procedures are completed. 
7.3 Removal of Subject from Study 
Subjects will be removed from the study when any of the criteria listed in Section 8.3 apply. The 
Principal Investigator will be notified, and treating physician will document the reason for study 
removal and the date the patient was removed in the subject’s medical record.  The study 
coordinator will record the reason for removal and date in the Case Report Form (CRF).  
8.0 
STUDY PROCEDURES 
8.1 Screening/Baseline Procedures 
GRID form of radiation therapy is a standard way of delivering radiation therefore no protocol-
specific procedures are required.   
8.2 Study Assessments: 
8.2.1 
Chemotherapy:  
 Subject will receive routine chemotherapy for osteosarcoma (unless subject has 
already received chemotherapy) 
 

Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
IRB #205993 
PI: Leslie Harrell, DO 
Sponsor:  UAMS 
 
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8.2.2 
Radiation Therapy: 
 Subject will receive GRID radiation therapy. GRID radiation therapy is considered 
a standard radiation therapy method however is not typically used in pediatric 
osteosarcoma patients. This protocol will evaluate whether or not the use of this 
therapy will provide benefit to this patient population.  
8.2.3 
Surgery: 
 Routine surgery for osteosarcoma 
 
8.2.4 
30 Day Post-Surgery visit (+/- 7 days): 
 Physical exam 
 Adverse Event (AE) assessment 
 
8.2.5 
90 day Post-Surgery visit (+/- 7 days):  
 Physical exam 
 Adverse Event (AE) assessment 
8.3 Removal of Subjects from Study 
Patients can be taken off the study at any time at their own request, or they may be withdrawn 
at the discretion of the investigator for safety, behavioral or administrative reasons. The reason(s) 
for discontinuation will be documented and may include:  
 
Patient voluntarily withdraws consent from study;  
 
Patient is unable to comply with protocol requirements; 
 
Patient experiences toxicity that makes continuation in the protocol unsafe; 
 
Treating physician judges continuation on the study would not be in the patient’s best 
interest; 
 
Patient becomes pregnant (pregnancy to be reported along same timelines as a serious 
adverse event). 
9.0 
MEASUREMENT OF EFFECT 
 
The effects of GRID radiotherapy will be determined by histological examination of the 
 
specimen(s) taken during surgery. 
 
10.0 
DEVICE INFORMATION 
 
GRID therapy is to be delivered using a commercially available linear accelerator (Varian 
 
Truebeam STX) equipped with a commercially available GRID block (Radiation Product Design 
 
GRID block for Varian 64.5cm MLC). The GRID block discretizes the radiation beam from the 
 
linear accelerator into multiple smaller beams. The GRID block is a passive beam modifier. That 
 
is, it remains static during the delivery of the GRID therapy. The intervening areas between the 
 
smaller discretized beams receive much lower doses of radiation as compared to the dose 

Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
IRB #205993 
PI: Leslie Harrell, DO 
Sponsor:  UAMS 
 
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within the small beam volume. This creates a valley and peak type dose distribution within the 
 
GRID target.  
11.0 
ADVERSE EVENTS 
11.1 Adverse Events Associated with GRID therapy 
The potential risks of using a GRID block for radiotherapy delivery are similar to those of 
radiation therapy using a standard multi-leaf collimator (MLC). The risks are not due to the use 
of the GRID block itself, but from the actual irradiation as is the case in standard MLC 
radiotherapy.  
 
Risks and side effects related to GRID therapy include: 
Likely: 
 
Skin reaction (redness) 
 
Hair loss in the treated area 
Less Likely: 
 
Fatigue 
 
Reductions in blood counts 
 
Treatment of large tumors with radiation, chemotherapy and surgery may results in 
infection or lack of healing which could result in prolonged hospitalization.  
Rare: 
 
Fibrosis (hardening of the tissues) 
 
Pain in the treated limb 
 
Swelling 
 
Fracture of bone 
 
Bruising of skin 
 
Neve damage 
 
Amputation 
 
There exists the potential risk for loss of confidentiality. Measures to protect the confidentiality 
of study particpants will be implemented as described in the Data Handling and Recordkeeping 
section.  
 
There will be no direct benefits to the study participants; however, knowledge gained from the 
study could potentially benefits patients in the future.  
11.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which is required as part of every clinical trial, is 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times during a trial. Additionally, certain adverse events must be reported in an expedited manner 
to allow for optimal monitoring of patient safety and care.  
All patients experiencing an adverse event will be monitored until the completion of the subject’s 
post-GRID visit:  
 
the adverse event resolves or the symptoms or signs that constitute the adverse event 

Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
IRB #205993 
PI: Leslie Harrell, DO 
Sponsor:  UAMS 
 
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return to baseline;  
 
there is a satisfactory explanation other than the study agent for the changes observed; 
or 
 
death. 
11.3 
Definitions 
11.3.1 Definition of Adverse Event 
An adverse event is any untoward medical occurrence in a patient undergoing study 
assessments and which does not necessarily have a causal relationship with the assessments. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the study assessments, 
whether or not related to the assessments.  
11.3.2 Severity of Adverse Events 
Adverse events will be graded according to the NCI Common Terminology Criteria for Adverse 
Events 
(CTCAE) 
version 
4.0. 
The 
CTCAE 
v4 
is 
available 
at 
http://ctep.cancer.gov/reporting/ctc.html 
11.3.3 Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any untoward medical 
occurrence that: 
 
Results in death. 
o If death results from (progression of) the disease, the disease should be reported as 
event (SAE) itself. 
 
Is life-threatening. 
o The patient was at risk of death at the time of the event; it does not refer to an event 
that hypothetically might have caused death if it were more severe. 
 
Requires in-patient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours. 
 
Results in persistent or significant disability or incapacity. 
 
Is a congenital anomaly/birth defect. 
 
Is an important medical event. 
Any event that does not meet the above criteria, but that in the judgment of the investigator 
jeopardizes the patient, may be considered for reporting as a serious adverse event. The event 
may require medical or surgical intervention to prevent one of the outcomes listed in the 
definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in an emergency room or 
at home; convulsions that may not result in hospitalization; development of drug abuse or 
drug dependency. 

Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
IRB #205993 
PI: Leslie Harrell, DO 
Sponsor:  UAMS 
 
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11.4 
Reporting Requirements for Adverse Events 
11.4.1 Expedited Reporting 
 
The Principal Investigator must be notified within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study.  
 
The UAMS IRB must be notified within 10 business days of “any unanticipated 
problems involving risk to subjects or others” (UPR/UPIRTSO; See UAMS IRB 
Policy 10.2). 
11.4.2 Routine Reporting 
All other adverse events, such as those that are expected, or are unlikely or definitely not 
related to the study participation, are to be reported annually as part of regular IRB continuing 
review. 
12.0 
STATISTICAL CONSIDERATIONS 
12.1 
Study Design/Study Endpoints 
 
This is a dose-escalation study with three radiation doses: 10Gy, 15Gy, and 20Gy. It uses 
the traditional “3+3” design to determine whether to escalate or de-escalate doses, and 
thereby to determine the maximum tolerated dose (MTD) on this protocol. The initial 
cohort of subjects will receive a 15Gy dose of GRID therapy, as shown in the diagram. The 
second cohort of subjects will receive either 20Gy or 10Gy of GRID, also as shown in the 
diagram.  
 
The study endpoint is dose-limiting toxicity (DLT), which is defined as a treatment-related 
AE of Grade 3 or higher. Subjects will be assessed at both their 30-day post-surgery visit 
and their 90-day post-surgery visit for presence of a DLT. 
INITIAL COHORT: 
 
Chemotherapy  
followed by therapy with 
GRID at 15Gy 
ESCALATION COHORT: 
 
Chemotherapy 
followed by therapy with 
GRID at 20Gy 
DE-ESCALATION COHORT: 
 
Chemotherapy 
followed by therapy with 
GRID at 10Gy 

Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
IRB #205993 
PI: Leslie Harrell, DO 
Sponsor:  UAMS 
 
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12.2 
Evaluation Plan 
 
Table 1 shows how the number of DLTs in the initial cohort of will be used to determine 
whether to escalate or de-escalate the GRID dose in the next cohort.  
Table 1: Toxicity Decision Rules for Initial Cohort (GRID at 15Gy) 
DLTs/ Cohort1 
Action 
0/3 
Begin accrual to Escalation Cohort 
1/3 
Expand Initial Cohort to 6 subjects 
1/6 
Begin accrual to Escalation Cohort 
2/6, 3/6, or 4/6 
Begin Accrual to De-Escalation Cohort 
2/3 or 3/3 
Begin Accrual to De-Escalation Cohort 
1 DLT = Dose-Limiting Toxicity 
 
If the second cohort is the Escalation cohort, then Table 2 shows how the number of DLTs 
will be used to determine the MTD on this protocol. 
Table 2: Toxicity Decision Rules for Escalation Cohort (GRID at 20Gy) 
DLTs/ Cohort1 
Action 
0/3 or 1/3 
Expand cohort to 6 subjects 
0/6 or 1/6 
Stop:  Declare escalation dose to be the MTD2 
2/6, 3/6, or 4/6 
Stop:  Previous dose level is the MTD2 
2/3 or 3/3 
Stop:  Previous dose level is the MTD2 
1 DLT = Dose-Limiting Toxicity 
2 MTD = Maximum Tolerated Dose 
 
On the other hand, if the second cohort is the De-Escalation cohort, then Table 3 shows 
how the number of DLTs will be used to determine whether 10Gy is at or above the MTD 
on this protocol. 
Table 3: Toxicity Decision Rules for De-Escalation Cohort (GRID at 10Gy) 
DLTs/ Cohort1 
Action 
0/3 or 1/3 
Expand cohort to 6 subjects. 
0/6 or 1/6 
Stop:  De-escalation dose level is the MTD2 
2/6, 3/6, or 4/6 
Stop:  De-escalation dose level is above MTD2 
2/3 or 3/3 
Stop:  De-escalation dose level is above MTD2 
1 DLT = Dose-Limiting Toxicity 
2 MTD = Maximum Tolerated Dose 
 
12.3 
Sample Size Estimation. If the MTD on this protocol is 10Gy, 15Gy, or 20Gy, then the 
above 3+3 dose-escalation design will find it using a minimum of 6 and maximum of 12 
subjects. On the other hand, if 10Gy is above the MTD on this protocol, then the above 3+3 
dose-escalation design will uncover that fact using a minimum of 6 and maximum of 12 
subjects. Therefore, the minimum number accrued to this protocol will be 6 subjects, while 
the maximum number accrued to this protocol will be 12 subjects. 
 
 

Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
IRB #205993 
PI: Leslie Harrell, DO 
Sponsor:  UAMS 
 
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13.0 
STUDY MANAGEMENT 
13.1 
Registration Procedures 
All patients must be registered with the Cancer Clinical Trials Office before enrollment to study. 
Prior to registration, eligibility criteria must be confirmed with the Research Staff. To register a 
patient, call CCTO Monday through Friday, 8:00AM-4:30PM.  
13.2 
Data Management 
13.3 
Data must be submitted according to protocol requirements for ALL subjects registered, 
whether or not study procedures are performed. For screen failures, only the eligibility 
criteria case report form will be completed. Data obtained during the study will be collected 
at each subject visit and entered into the protocol database. Subjects will be registered in 
RPRS, a cancer Biomedical Informatics Grid (caBIG®, NCI) application. Data will be entered 
into OpenClinica through electronic web-based case report forms (CRFs). OpenClinica is a 
secure open source system for electronic data capture and clinical data management. All 
information in OpenClinica will be coded with a unique identifier and will be stored in the 
database indefinitely.  In the event that a subject fails screening, only the eligibility criteria 
case report form will be completed. The Principal Investigator will carefully monitor study 
procedures to protect the safety of research subjects, the quality of the data and integrity 
of the study. Monitoring and Auditing 
13.3.1 Medical Monitor:  
The Medical Monitor, Principal Investigators and study staff will meet to review safety data 
after each of the Data Monitor periodic visit. 
13.3.2 Data Monitor:  
UAMS is the Sponsor. One (or more) Data Monitor(s) will be appointed by the monitoring 
division of the UAMS Office of Research regulatory Affairs (ORRA) to assure that the rights 
and well-being of human subjects are protected, that the data are accurate, complete and 
verifiable from source documents and that the trial is conducted in compliance with currently 
approved protocol/amendments, with GCP, and with the applicable regulatory requirements 
set forth in 21 CFR 312. 
The Data Monitor(s) will be familiar with the protocol, the informed consent form, any other 
information provided to the subjects, SOPs, GCP and applicable regulatory requirements. 
Data Monitor(s) will have access to research subjects’ medical records and other study-
related records. The investigator agrees to cooperate with the study coordinator and Medical 
Monitor to ensure that any problems detected in the course of these monitoring visits are 
resolved.  Personal contact between the Data Monitor, Medical Monitor, study staff and the 
investigator will be maintained throughout the clinical trial to assure that the investigator is 
fulfilling his/her obligations and that the facilities used in the clinical trial remain acceptable. 
13.3.3 Research Subject Safety and Stopping Rules:  
If 2 SAEs occur with attribution to the study, the trial will be suspended until further review is 
completed by the Medical Monitor, PI, sponsor and FDA. This will be accomplished by the 

Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
IRB #205993 
PI: Leslie Harrell, DO 
Sponsor:  UAMS 
 
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study team, the PI, Co-PI, biostatistician, Medical Monitor and CRA, either at the regular 
meeting or a special meeting called by the Medical Monitor or the PI because of the SAEs. 
 
13.4 
Ethical Considerations 
This study will be conducted in accordance with all applicable government regulations and 
University of Arkansas for Medical Sciences research policies and procedures.  This protocol and 
any amendments will be submitted and approved by the UAMS Institutional Review Board (IRB) 
to conduct the study.   
The formal consent of each subject, using the IRB-approved consent form, will be obtained before 
that subject is submitted to any study procedure.  All subjects for this study will be provided a 
consent form describing this study and providing sufficient information in language suitable for 
subjects to make an informed decision about their participation in this study.  The person 
obtaining consent will thoroughly explain each element of the document and outline the risks and 
benefits, alternate treatment(s), and requirements of the study.  The consent process will take 
place in a quiet and private room, and subjects may take as much time as needed to make a 
decision about their participation.  Participation privacy will be maintained and questions 
regarding participation will be answered.  No coercion or undue influence will be used in the 
consent process.  This consent form must be signed by the subject or legally authorized 
representative (only if applicable), and the individual obtaining the consent.  A copy of the signed 
consent will be given to the participant, and the informed consent process will be documented in 
each subject’s research record.  If assent is required, include a statement that assent will be 
obtained and that assenting minors will be consented if they reach the age of majority during the 
study (if applicable). 
13.5 
Dissemination of Data 
Results of this study may be used for presentations, posters, or publications. The publications will 
not contain any identifiable information that could be linked to a participant.  
 
 

Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
IRB #205993 
PI: Leslie Harrell, DO 
Sponsor:  UAMS 
 
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REFERENCES 
1) Bielack SS, Kempf-Bielack B, Delling G, et al. Prognostic factors in high-grade osteosarcoma 
of the extremities or trunk: an analysis of 1,702 subjects treated on neoadjuvant 
cooperative osteosarcoma study group protocols. Journal of Clinical Oncology, 2002. 20: 
776-790. 
2) Whelan J, Weeden S, Uscinska B, et al. Localised extremity osteosarcoma: Mature survival 
data from two European Osteosarcoma Intergroup randomised clinical trials. Proceedings of 
the American Society of Clinical Oncology, 2000. 19: 1281a. 
3) Meyers PA, Schwartz CL, Krailo M, et al. Osteosarcoma: A randomized, prospective trial of 
the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin and high dose 
methotrexate . Journal of Clinical Oncology 2005; 23(9): 2004-2011. 
4) Marina N, Bernstein M and Krailo M. A Randomized Trial of the European and American 
Osteosarcoma Study Group to Optimize Treatment Strategies for Resectable Osteosarcoma 
Based on Histological Response to Pre-Operative Chemotherapy: A Phase III Intergroup 
Study. Children’s Oncology Group (COG) Clinical Trial AOST 0331. 
5) Mohiuddin, M., Curtis DL, Grizos WT, et al., Palliative treatment of advanced cancer using 
multiple nonconfluent pencil beam radiation. A pilot study. Cancer, 1990. 66(1): 114-118. 
6) Mohiuddin, M., Fujita M, Regine WF, et al., High-dose spatially-fractionated radiation 
(GRID): a new paradigm in the management of advanced cancers. Int J Radiat Oncol Biol 
Phys, 1999. 45(3): 721-727. 
7) Huhn, J.L., Regine WF, Valentino JP, et al., Spatially fractionated GRID radiation treatment of 
advanced neck disease associated with head and neck cancer. Technol Cancer Res Treat, 
2006. 5(6): 607-612. 
8) Reiff, J.E., Huq MS, Mohiuddin M, et al., Dosimetric properties of megavoltage grid therapy. 
Int J Radiat Oncol Biol Phys, 1995. 33(4): 937-942. 
9) Trapp, J.V., Warrington AP, Partridge M, et al., Measurement of the three-dimensional 
distribution of radiation dose in grid therapy. Phys Med Biol, 2004. 49(19): N317-N323. 
10) Ha, J.K., Zhang G, Naqvi SA, et al., Feasibility of delivering grid therapy using a multileaf 
collimator. Med Phys, 2006. 33(1): 76-82. 
11)  Peñagarícano JA, Moros EG, Ratanatharathorn V, Yan Y, Corry P.Evaluation of Spatially 
Fractionated Radiotherapy (GRID) and Definitive Chemoradiotherapy with Curative Intent 
for Locally Advanced Squamous Cell Carcinoma of the Head and Neck: Initial Response Rates 
and Toxicity. Int J Radiat Oncol Biol Phys. 2010. In-press. 
12)  Zwicker RD, Meigooni A and Mohiuddin M. Therapeutic advantage of GRID irradiation for 
large single fractions. Intenatonal Journal of Radiation Biology and Physics, 2004. 
58(4):1309-1315. 
 

 
Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
                     IRB #205993 
Site: UAMS 
Sponsor: UAMS 
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CONSENT FORM 
AND  
INFORMATION ABOUT 
 
Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
 
TO BE CONDUCTED AT 
UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES 
 
(Principal Investigator: Leslie Harrell, DO) 
 
 
 
 
 
 
 
 
 
              
 
 
 
 
 
SUBJECT NAME  
 
 
 
          
  HOSPITAL I.D. NUMBER 
 
 
INTRODUCTION 
This is a clinical trial, a type of research study being conducted at the University of Arkansas for Medical Sciences 
(UAMS). This research is being sponsored by UAMS. Your doctor will explain the clinical trial to you. Clinical trials 
include only people who choose to take part. Please take your time to make your decision about taking part. You 
may discuss your decision with your friends and family. You can also discuss it with your health care team. If you 
have any questions, you can ask your research doctor for more information. 
 
You are being asked to take part in this research study because you have osteosarcoma. 
 
WHY IS THIS RESEARCH BEING DONE? 
The main purpose of this research study is to evaluate the safety of three dose levels of GRID radiotherapy in 
pediatric osteosarcoma. The safety of GRID radiotherapy is well understood in adult patients but not in pediatric 
patients. GRID radiotherapy is a descriptive term for Spatially Fractionated Radiotherapy. This pattern is similar to a 
checkerboard where every other space is exposed to radiation. This type of radiation is common in other types of 
diseases but has never been tested in osteosarcoma pediatric patients. This device is experimental and is not 
approved by the FDA for use in this disease.  
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
We will enroll up to 12 patients, ages 5 -21 years of age.   
 
 

 
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Sponsor: UAMS 
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WHAT WILL HAPPEN DURING THIS STUDY? 
The required portion of the study is split into four parts.  These are only required for participation in this study and 
will not affect your care at UAMS.  Delivery of GRID radiotherapy requires only one dose of radiation. The time to 
deliver this one dose of radiation is approximately 25 minutes. After this one dose of radiation you will continue with 
standard osteosarcoma therapy under the care of your pediatric oncologist and surgeon. Return visits to the 
Radiation Oncology Center will be needed to assess the safety of GRID therapy. 
At the beginning of the research, 3 research participants will be treated with a dose of GRID radiotherapy. If this 
does not cause any side effects, the dose will be made higher as new research participants take part in the study. If 
there are too many side effects, the next group of participants will receive a lower dose. 
 
Chemotherapy 
o 
You will receive routine chemotherapy for osteosarcoma unless you have already finished 
chemotherapy (You will receive the same chemotherapy you would get even if you don’t join the 
study. Your chemotherapy regimen and scheduling will be determined by your doctor) 
 
Radiation therapy 
o 
You will receive radiation therapy through the experimental GRID technique (research procedures) 
 
Surgery 
o 
You will receive routine surgery for osteosarcoma (You will receive the same surgery you would 
get even if you don’t join the study. Your surgery will be determined by your doctor) 
 Follow-up (research procedures) 
o 
30 Day Post-Surgery visit 
 
Physical examination 
 
Adverse Event (side effects) assessment 
o 
90 Day Post-Surgery visit 
 
Physical examination 
 
Adverse Event (side effects) assessment 
 
HOW LONG WILL I BE IN THE RESEARCH? 
The approximate length of complete study participation will be around 12 months. This timeframe begins at the 
time of consent and ends upon completion of the 90 day post-surgery visit. Participation in this study will require 
two extra visits than routine care would require (30 day and 90 day post-surgery).  
 
WHAT OTHER CHOICES DO YOU HAVE IF YOU DECIDE NOT TO TAKE PART? 
Being part of this study is voluntary.  This means you can decide to say yes or no to being part of this study.  Neither 
decision will affect your present or future medical care.  This informed consent may contain words you do not 
understand.  You are free to ask as many questions as you like before you decide whether you want to participate 

 
Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
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Site: UAMS 
Sponsor: UAMS 
Version 9 
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in this research study.  You are free to ask questions at any time before, during, or after your participation in this 
research.  You will not incur a penalty or loss of benefits if you refuse to participate or withdraw early from the study. 
If you choose not join the study, you can seek other kinds of treatment for your disease. Your doctor can explain 
your treatment choices to you.  
If you agree to take part in this study, you must sign this consent form.  A signed copy of the consent form will be 
given to you.  You are not waiving any legal right by signing this consent form. 
 
CAN I STOP BEING IN THE RESEARCH? 
Yes. You can decide to stop at any time. Contact the research staff and/or Principal Investigator if you decide to stop 
your participation. If you decide to end your participation early, the information already collected before your 
withdrawal will continue to be used and will not be removed from the study database. 
In addition, your physician may stop you from taking part in the study at any time if he/she believes that is it in your 
best interest; if you do not follow the study rules; or if the study is stopped. This may happen without your consent.  
 
WILL I BE COMPENSATED FOR TAKING PART IN THIS STUDY? 
You will not receive any form of compensation or payment for your participation in this research. 
 
WHAT WILL IT COST YOU TO TAKE PART IN THIS STUDY? 
The radiation therapy provided in this study will be paid for by the research study and will not be billed to your 
insurance company. Some of the tests or treatments (i.e. chemotherapy and surgery) used in this study may be part 
of standard care used to maintain your health even if you did not take part in this study.  You or your insurance 
company may be responsible for the cost of this standard care.  It is possible that your insurance company may deny 
paying for any tests and procedures related to a research study, making you responsible for any charges. You will be 
responsible for normal co-pays, deductibles and non-covered services that are not the responsibility of the study. 
There is never any guarantee with any hospital service that you will not incur some financial responsibility. Staff is 
available to assist with talking to your insurance company to review your specific benefits and coverage before 
deciding to participate. All trial-related costs that are done solely for research purposes will be provided at no cost 
to you.  
 
WHAT ARE THE POTENTIAL BENEFITS TO ME IF I TAKE PART IN THIS STUDY? 
There are no direct benefits for the participants volunteering to take part in the study.  Knowledge gained from this 
study could potentially benefit patients in the future. 
 
WHAT ARE THE RISKS IF I TAKE PART IN THIS STUDY? 
Radiation Therapy is part of the standard care that has been recommended by your physician. In this study we are 
evaluating a new technique to deliver the radiation. This technique is called a GRID procedure. Utilizing this 
technique is common in other types of cancer but has not been tested in pediatric osteosarcoma patients. Your 

 
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Site: UAMS 
Sponsor: UAMS 
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physician will discuss the risk associated with GRID procedure with you before the procedure. The potential risks of 
using a GRID block for radiation therapy are similar to those of regular radiation therapy. This study may involve risks 
that are currently unknown. The risks described below are not due to the use of the GRID block itself, but from the 
actual irradiation as is the case in standard therapy.  
Likely 
 
Skin reaction (redness) 
 
Hair loss in the treated area 
Less Likely 
 
Fatigue  
 
Reductions in blood counts 
 
Treatment of large tumors with combined radiation, chemotherapy and surgery may result in infection or 
lack of healing which could result in prolonged hospitalization 
Rare 
 
Fibrosis (hardening of the tissues) 
 
Pain in the treated limb 
 
Swelling 
 
Fracture of bone 
 
Bruising of skin 
 
Nerve damage 
 
Amputation 
Another potential risk to study participants is the potential for loss of confidentiality.  The Principal Investigator will 
carefully monitor study procedures to protect the safety of research subjects, the quality of the data and the integrity 
of the study. Research records will be stored in a locked area with access to study personnel only.   
 
WHAT IF I AM INJURED WHILE PARTICIPATING IN THIS RESEARCH? 
In the event you are hurt by being in this research, treatment will be available. This treatment may include: first aid, 
emergency treatment, and/or follow-up care. This treatment may be billed to you or your insurance company in the 
normal manner. Normally, no other form of compensation is available. If you think you have been hurt by this 
research, let the Principal Investigator know right away by calling Leslie Harrell, DO at (501) 526-6591. After hours 
you may reach the oncology physician on call at (501) 686-8530.  
 
WILL MY MEDICAL INFORMATION REMAIN CONFIDENTIAL? 
We will do our best to make sure the personal information in your medical record will be kept private. However, we 
cannot guarantee total privacy. Your personal information may be given out if required by law. If information from 
this study is published or presented at scientific meetings, your name and other personal information will not be 
used. Participants may be identified by study numbers only on all research documents. The connection with the 
participants name will be kept by research personnel in a locked facility. Records for this research study will be 
retained indefinitely.  

 
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Site: UAMS 
Sponsor: UAMS 
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A record of your participation in this research will be maintained, but this record will be kept confidential to the 
extent allowed by law.  The results of this study may be published in a medical journal, but you will not be identified 
by name.  Representatives of the UAMS Institutional Review Board (IRB), other institutional oversight offices, the 
Food and Drug Administration and the Office for Human Research Protections (OHRP) may be given access to 
research study records and pertinent medical records that may contain your name or other identifying information.   
By law, the study team must release certain information to the appropriate authorities if at any time during the 
study there is concern that child abuse or elder abuse has possible occurred or you disclose a desire to harm yourself 
or others. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web 
site will not include information that can identify you. At most, the Web site will include a summary of the results. 
You can search this Web site at any time. 
 
WHAT ARE MY RIGHTS IF I TAKE PART IN THIS RESEARCH? 
Taking part in this research is your choice. You may choose either to take part or not to take part in the research. If 
you decide to take part in this study, you may leave the study at any time. No matter what decision you make, there 
will be no penalty to you and you will not lose any of your regular benefits. Your relationship with your doctor or 
with UAMS will not be affected by not participating or leaving the research. Leaving the research will not affect your 
medical care. You can still get your medical care from our institution. 
We will tell you about new information or changes in the study that may affect your health or your willingness to 
continue in the study. In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form. You can refuse to sign this form.  If you do not sign this form you will not be able to 
take part in this research study. However, your health care and benefits outside of this study will not change. 
 
WHO CAN ANSWER MY QUESTIONS ABOUT THE RESEARCH? 
If you have any questions, concerns or complaints about this study, call Leslie Harrell, DO at (501) 526-6591. 
If you have questions about your rights, general questions, complaints, or issues as a person taking part in this study, 
call the UAMS IRB at (501) 686-5667.  You are also encouraged to call this number if you wish to speak with someone 
not directly related to this study. 
 
 
 
 
 
 
 
 

 
Phase I clinical trial of GRID therapy in pediatric osteosarcoma of the extremity 
 
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Sponsor: UAMS 
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STATEMENT OF PARTICIPANT 
I have been told that I will be given a copy of this form. I have read it or it has been read to me. I understand the 
information and have had my questions answered. I understand my participation in this study is voluntary. I agree 
to take part in this study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Signature 
 
 
 
 
 
 
 
Date & Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
Person Obtaining Consent Signature 
 
 
 
 
 
Date & Time