Conditions: Recurrent Glioblastoma
Keywords: ChemoID Cancer stem cells Drug response assay Glioblastoma Brain Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 78
Healthy volunteers: no

Brief summary:
The purpose of this clinical study is to confirm the utility of chemosensitivity tumor testing on cancer stem cells (ChemoID) as a predictor of clinical response in poor prognosis malignant brain tumors such as recurrent glioblastoma (GBM).

Detailed description:
This study is designed as a parallel group randomized controlled clinical trial to determine if recurrent Glioblastoma (GBM) patients treated with drugs predicted by the ChemoID assay will have better outcomes than patients treated with standard-of-care control therapy chosen by the Physician.

Upon obtaining informed consent, all eligible participants affected by recurrent GBM will have a tumor biopsy to undergo ChemoID drug response testing with multiple FDA-approved chemotherapeutic agents.

Eligible participants will be randomized to a standard treatment arm with control treatment (chemotherapy chosen by the Physician from a provided list), or to a study arm of FDA-approved drugs selected by the ChemoID drug response assay.

Arms:
arm 1: Participants will be treated with control chemotherapy treatment (standard-of-care chemotherapy chosen by the Physician from the provided list).

Control chemotherapy treatment will be chosen from any of the following standard-of-care chemotherapy drugs or combinations:

* Carboplatin;
* Irinotecan;
* Etoposide;
* BCNU;
* CCNU;
* Temozolomide;
* Procarbazine;
* Vincristine;
* Imatinib;
* Procarbazine, CCNU, Vincristine;
* Carboplatin, Irinotecan;
* Carboplatin, Etoposide;
* Temozolomide, Etoposide;
* Temozolomide, Imatinib. The treating physician will NOT receive the ChemoID assay results from the ChemoID lab. arm 2: Participants will be treated with ChemoID-guided standard-of-care chemotherapy drugs from the provided list.

ChemoID-guided treatment will be chosen from the following standard-of-care chemotherapy drugs or combinations:

* Carboplatin;
* Irinotecan;
* Etoposide;
* BCNU;
* CCNU;
* Temozolomide;
* Procarbazine;
* Vincristine;
* Imatinib;
* Procarbazine, CCNU, Vincristine;
* Carboplatin, Irinotecan;
* Carboplatin, Etoposide;
* Temozolomide, Etoposide;
* Temozolomide, Imatinib.

The treating physician will receive the ChemoID assay results from the ChemoID lab.

Interventions: intervention 1: ChemoID assay intervention 2: Chemotherapy
Intervention descriptions: intervention 1: The ChemoID test is a CLIA-certified and CAP-accredited drug response assay performed by a hospital clinical pathology laboratory that uses a patient's live tumor cells to indicate which chemotherapy agent (or combinations) will kill not only bulk of tumor cells, but importantly the cancer stem cells (CSCs) that are known to cause cancer to recur. During the assay, cancer stem cells and bulk tumor cells from an individual patient are exposed to FDA-approved chemotherapy drugs.

The test measures the cytotoxic effect of actual doses of standard-of-care chemotherapies. The ChemoID drug response assay reports a prioritized list of effective and ineffective chemotherapies. The test is designed to target cancer stem cells to mitigate tumor relapse. intervention 2: Chemotherapies chosen by Physician or ChemoID assay are in the same list of FDA approved drugs to treat recurrent high-grade glioma

Protocol document:
Prot_SAP_ICF_001.pdf: 
 
 
 
 
Title: 
 
 
 
 
 
 
 
 
Type of Clinical Trial 
 
Drug or Device 
Name(s): 
 
FDA IND or IDE 
 
Sponsor: 
 
 
 
 
 
 
            
 
 
 
 
            
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Approved WIRB® Protocol #20172720 
  
 
 Standard Chemotherapy versus Chemotherapy Chosen by Cancer
 Stem Cell Chemosensitivity Testing in the Management of Patients
 with Recurrent Glioblastoma Multiforme (GBM) and recurrent
 WHO Grade III Glioma 
Pivotal Randomized Clinical Trial
ChemoID Drug Response Assay
 
  
N/A 
Cordgenics, LLC
IRB Protocol  
 
20172720
 
 
 
  
 
01/04/2018 
 
 
 
 
Approval Date:
 
ClinicalTrials.gov  
      NCT03632135


 
 
 
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TABLE OF CONTENTS 
Table of Contents ................................................................................................................... ii 
Abbreviations and Definitions of Terms .............................................................................. v 
Abstract ................................................................................................................................ vii 
Protocol Synopsis ................................................................................................................... x 
Table 1: Schedule of Study Procedures ........................................................................... xvii 
Study Diagram .................................................................................................................... xix 
1 
BACKGROUND INFORMATION AND RATIONALE ....................................................................... 1 
1.1 
INTRODUCTION ..................................................................................................................................... 1 
1.2 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR INTERVENTION ..................................... 3 
1.3 
FINDINGS FROM NON-CLINICAL AND CLINICAL STUDIES ..................................................................... 3 
1.3.1 
Clinical Studies ............................................................................................................................... 3 
1.4 
SELECTION OF DRUGS AND DOSAGES ................................................................................................... 5 
1.5 
RELEVANT LITERATURE AND DATA ..................................................................................................... 5 
1.6 
COMPLIANCE STATEMENT .................................................................................................................... 7 
2 
STUDY OBJECTIVES .............................................................................................................................. 9 
2.1 
PRIMARY OBJECTIVE (OR AIM) ............................................................................................................ 9 
2.2 
SECONDARY OBJECTIVES (OR AIMS) .................................................................................................... 9 
3 
INVESTIGATIONAL PLAN .................................................................................................................... 9 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ................................................................................................. 9 
3.1.1 
Screening Phase .............................................................................................................................. 9 
3.1.2 
Study Treatment Phase 1 (start of the study intervention) .............................................................. 9 
3.1.3 
Study Treatment Phase 2 ............................................................................................................... 10 
3.1.4 
Study Treatment Phase 3 ............................................................................................................... 10 
3.1.5 
Follow-up Phase ........................................................................................................................... 10 
3.2 
ALLOCATION TO TREATMENT GROUPS AND BLINDING ...................................................................... 11 
3.3 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ................................................................. 11 
3.3.1 
Duration of Study Participation .................................................................................................... 11 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected ................................................ 11 
3.4 
STUDY POPULATION ........................................................................................................................... 12 
3.4.1 
Inclusion Criteria .......................................................................................................................... 12 
3.4.2 
Exclusion Criteria ......................................................................................................................... 12 
4 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE ....................................... 13 
4.1 
TREATMENT PLAN .............................................................................................................................. 13 
4.2 
DURATION OF THERAPY ..................................................................................................................... 13 
4.3 
TREATMENT WINDOW ........................................................................................................................ 14 
4.4 
ARM 1 - PHYSICIANS CHOICE OF CHEMOTHERAPY REGIMENS ........................................................... 15 
4.5 
ARM 2 – CHEMOID DRUG RESPONSE ASSAY CHEMOTHERAPY REGIMENS ........................................ 15 
4.6 
DURATION OF STUDY ......................................................................................................................... 15 
4.7 
FOLLOW-UP AFTER STUDY TREATMENT DISCONTINUATION AND/OR PROGRESSION ............................ 16 
5 
STUDY PROCEDURES .......................................................................................................................... 16 
5.1 
SCREENING VISIT ............................................................................................................................... 16 
5.2 
ENROLLMENT CONTINGENCY PLANS ................................................................................................. 17 
5.3 
STUDY TREATMENT PHASE ................................................................................................................ 17 
5.3.1 
Visit 1 – pre-op visit ...................................................................................................................... 18 
5.3.2 
Visit 2 post-op visit ........................................................................................................................ 18 
5.3.3 
Visit 3 post-radiation visit ............................................................................................................. 18 
5.3.4 
Visit 4 start of treatment visits ....................................................................................................... 19 


 
 
 
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5.4 
FOLLOW-UP PHASE ............................................................................................................................. 19 
5.4.1 
Visit 1 ............................................................................................................................................ 20 
5.4.2 
Visit 2 ............................................................................................................................................ 20 
5.4.3 
Visit 3 ............................................................................................................................................ 20 
5.4.4 
Visit 4 ............................................................................................................................................ 21 
5.4.5 
Visit 5 ............................................................................................................................................ 21 
5.4.6 
Visit 6 ............................................................................................................................................ 22 
5.4.7 
Visit 7 ............................................................................................................................................ 22 
5.4.8 
Visit 8 ............................................................................................................................................ 22 
5.4.9 
Visit 9 ............................................................................................................................................ 23 
5.4.10 
Visit 10 ...................................................................................................................................... 23 
5.4.11 
Visit 11 ...................................................................................................................................... 23 
5.4.12 
Visit 12: ..................................................................................................................................... 24 
5.4.13 
Visits 13 to 23 ........................................................................................................................... 24 
5.4.14 
Visit 24 ...................................................................................................................................... 24 
5.4.15 
Follow-up phone calls .............................................................................................................. 25 
5.5 
UNSCHEDULED VISITS ........................................................................................................................ 25 
5.6 
CONCOMITANT MEDICATION ............................................................................................................. 25 
5.7 
RESCUE MEDICATION ADMINISTRATION ............................................................................................ 25 
5.8 
SUBJECT COMPLETION/WITHDRAWAL ............................................................................................... 25 
5.8.1 
Early Termination Study Visit ....................................................................................................... 26 
6 
STUDY EVALUATIONS AND MEASUREMENTS ............................................................................ 26 
6.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS ................................................ 26 
6.1.1 
Medical Record Review ................................................................................................................. 26 
6.1.2 
Physical Examination .................................................................................................................... 27 
6.1.3 
Vital Signs ..................................................................................................................................... 27 
6.1.4 
Laboratory Evaluations................................................................................................................. 27 
6.1.5 
Other Evaluations, Measures ........................................................................................................ 27 
6.2 
EFFICACY EVALUATIONS ................................................................................................................... 28 
6.3 
SAFETY EVALUATION ......................................................................................................................... 28 
7 
STATISTICAL CONSIDERATIONS .................................................................................................... 28 
7.1 
PRIMARY ENDPOINT ........................................................................................................................... 28 
7.2 
SECONDARY ENDPOINTS .................................................................................................................... 28 
7.3 
STATISTICAL METHODS ...................................................................................................................... 29 
7.3.1 
Baseline Data ................................................................................................................................ 29 
7.3.2 
Efficacy Analysis ........................................................................................................................... 29 
7.3.3 
Safety Analysis .............................................................................................................................. 29 
7.4 
SAMPLE SIZE AND POWER .................................................................................................................. 29 
7.5 
INTERIM ANALYSIS ............................................................................................................................ 30 
8 
STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) .................... 31 
8.1 
DESCRIPTION ...................................................................................................................................... 31 
9 
SAFETY MANAGEMENT ..................................................................................................................... 32 
9.1 
CLINICAL ADVERSE EVENTS .............................................................................................................. 32 
9.1.1 
Definition of an Adverse Event (AE) ............................................................................................. 32 
9.2 
ADVERSE EVENT REPORTING ............................................................................................................. 37 
10 
STUDY ADMINISTRATION ........................................................................................................ 37 
10.1 
TREATMENT ASSIGNMENT METHODS ................................................................................................. 37 
10.1.1 
Randomization .......................................................................................................................... 37 
10.1.2 
Blinding..................................................................................................................................... 37 
10.1.3 
Unblinding ................................................................................................................................ 37 
10.2 
DATA COLLECTION AND MANAGEMENT ............................................................................................ 38 


 
 
 
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10.3 
CONFIDENTIALITY .............................................................................................................................. 38 
10.4 
REGULATORY AND ETHICAL CONSIDERATIONS .................................................................................. 38 
10.4.1 
Data and Safety Monitoring Plan ............................................................................................. 39 
10.4.2 
Risk Assessment ........................................................................................................................ 39 
10.4.3 
Potential Benefits of Trial Participation ................................................................................... 40 
10.4.4 
Risk-Benefit Assessment ............................................................................................................ 40 
10.5 
RECRUITMENT STRATEGY .................................................................................................................. 41 
10.6 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ............................................................ 41 
11 
PUBLICATION OF CLINICAL DATA ....................................................................................... 42 
12 
REFERENCES ................................................................................................................................ 43 
Appendix ............................................................................................................................... 44 
 
 
 


 
 
 
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ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
°C 
Degrees centigrade 
AE 
Adverse event 
CAP 
College of American Pathologists 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
CRF 
Case Report Form 
CSM 
Centers for Medicare & Medicaid Services 
DCC 
Data Coordinating Center 
DICOM 
Digital Imaging and Communications in Medicine 
DRE 
Disease-Related Event 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
FDA 
Food and Drug Administration 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 


 
 
 
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ISM 
Independent Safety Monitor 
LDT 
 Laboratory Developed Test 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
RANO 
Response Assessment in Neuro-Oncology Criteria 
SAE 
Severe Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 


 
 
 
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ABSTRACT 
Context:  (Background) 
The purpose of this clinical study is to confirm the utility of chemosensitivity tumor testing 
on cancer stem cells (ChemoID) as a predictor of clinical response in poor prognosis 
malignant brain tumors such as recurrent glioblastoma (GBM) and recurrent WHO III 
Glioma.  At recurrence, a minority of patients is eligible for second surgery or re-irradiation, 
based on appropriate patient selection.   
For the chemotherapy portion of their treatment, the management of recurrent glioblastoma 
and WHO III Glioma continues to be a moving target as new therapeutic principles enrich 
the standards of care for newly diagnosed disease.  Recurrent or progressive glioblastoma 
and recurrent WHO III Glioma are most commonly treated with nitrosoureas, 
temozolomide, CPT-11, bevacizumab, and/or combinations of these agents. 
Patients with recurrent GBM and recurrent WHO III Glioma will receive standard therapy 
consisting of surgical resection and/or biopsy as dictated by whether or not they are 
resectable and for the chemotherapy portion of their treatment participants will be 
randomized between treatments chosen by the physician (standard of care) or medications 
selected by the chemo-sensitivity drug assay. 
The idea is similar to when we test for bacterial sensitivity against antibiotics in case of a 
bacterial infection. The ChemoID test utilizes sample specimens obtained following 
standard of care indicated surgical resection and/or biopsy for the treatment of brain cancer. 
Objectives: (primary and important secondary objectives) 
The primary objective of this study is to compare patients with recurrent GBM and WHO 
grade III gliomas receiving standard of care versus chemosensitivity assay-guided 
chemotherapy for the chemotherapy portion of their therapy: 
• Median Overall Survival (OS). 
The secondary objectives of this study are to compare: 
• Overall Survival at 6, 9 and 12 months (OS6mo, OS9mo, OS12mo) 
• Median Progression Free Survival (PFS)  
• Progression Free Survival at 4, 6, 9, and 12 months (PFS4mo, PFS6mo, PFS9mo, PFS12mo) 
• Objective tumor response measured by RANO (Response Assessment in Neuro-
Oncology Criteria) 
• Time to recurrence 
• Health-Related Quality of Life (HRQOL)  
 
 
 


 
 
 
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Study Design:  
Basic design: Parallel Group Randomized Controlled Clinical Trial. 
Eligible patients with recurrent resectable GBM (who undergo surgical resection or a 
biopsy) and recurrent WHO grade III glioma will be consented to the trial.  Specimens will 
be evaluated for cancer stem cell chemosensitivity testing (ChemoID). 
Participants will be registered to the trial and randomized to either (ARM 1) standard of 
care chemotherapy chosen by physician, or (ARM 2) ChemoID-guided therapy as depicted 
in the schema below: 
  
 
 
 
Setting/Participants: 
The primary settings for this study are: 
1. 
Allegheny Health Network, Pittsburgh, PA 
2. 
University of Mississippi Medical Center, Jackson, MS 
3. 
Univ. of Cincinnati Brain Tumor Center, Cincinnati, OH 
4. 
Penn State Hershey Neuroscience Institute, Hershey, PA 
5. 
The University of Toledo, Eleanor N. Dana Cancer Center, Toledo, OH 
6. 
Charleston Area Medical Center, Charleston, WV 
7. 
Maine Medical Center Research Institute, Scarborough, ME 
8. 
Providence Brain and Spine Institute, Portland, OR 
9. 
Thomas Jefferson University Hospital, Philadelphia, PA 
10. 
St. Luke’s University Health Network, Bethlehem, PA 


 
 
 
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11. 
Louisiana State University Health Sciences Center, New Orleans, LA 
12. 
Kaiser Permanente, Los Angeles, CA 
13. 
University of Southern California, Los Angeles, CA 
 
 
Study Interventions and Measures:  
Primary study outcome measure:  To evaluate median overall survival (OS) in recurrent 
GBM patients who have had a ChemoID assay-guided treatment compared to standard 
therapy chosen by the physician. 
Secondary outcome measures: Evaluate if recurrent GBM patients treated with drugs 
predicted by the ChemoID drug response assay will have better additional outcomes as 
compared to patients treated with standard of care drugs by measuring: 
• Overall Survival at 6, 9 and 12 months (OS6mo, OS9mo, OS12mo) 
• Median Progression Free Survival (PFS)  
• Progression Free Survival at 4, 6, 9, and 12 months (PFS4mo, PFS6mo, PFS9mo, PFS12mo) 
• Objective tumor response measured by RANO (Response Assessment in Neuro-
Oncology Criteria) 
• Time to recurrence 
• Better Health-Related Quality of Life (HRQOL) as an outcome measure to ChemoID 
treatment selection using self-reported, and validated questionnaires, addressing 
physical, psychological, emotional, and social issues. 


 
 
 
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PROTOCOL SYNOPSIS 
Standard treatment with temozolomide and radiotherapy for patients with newly diagnosed 
glioblastoma has increased the median overall survival and, more importantly, the 2-year 
survival rate of patients. However, as yet, no investigations have been conducted to define 
effective strategies against recurrence, which occurs in most patients following combined 
radiotherapy/temozolomide treatment. As a consequence, recurrent glioblastoma (GBM) 
WHO Grade IV patients have a poor prognosis.   
At recurrence, a minority of patients is eligible for second surgery or re-irradiation, based on 
appropriate patient selection.  For the chemotherapy portion of their treatment, the 
management of recurrent glioblastoma continues to be a moving target as new therapeutic 
principles enrich the standards of care for newly diagnosed disease.  Recurrent or 
progressive glioblastoma is most commonly treated with nitrosoureas, temozolomide, CPT-
11, bevacizumab, and/or combinations of these agents. 
The drug sensitivity assay ChemoID is a CLIA certified and CAP accredited clinical 
laboratory functional test that uses patient’s live tumor cells to indicate which chemotherapy 
agent (or combinations) will kill not only cancer cells, but also more importantly the cancer 
stem cells (CSCs) that are known to cause cancer to recur.  Targeting of CSCs alongside the 
bulk of other cancer cells is a new paradigm in cancer treatment. 
Upon obtaining informed consent, participants with recurrent GBM who can be surgically 
resected will be registered to the trial and have tumor biopsy samples undergo CSCs 
chemosensitivity testing with multiple FDA approved chemotherapeutic agents. 
Participants will be randomized to either:  
(ARM 1) standard of care chemotherapy chosen by the physician 
or 
(ARM 2) ChemoID-guided therapy. 
Participants will be assessed by either brain MRI with contrast or CT scan with contrast at 2-
3 month intervals after therapies as per standard-of care. 
Results of clinical response to standard of care therapy or to ChemoID guided chemotherapy 
agents will be used to determine the predictive value of chemosensitivity testing in recurrent 
GBM patients as follows:  
Primary endpoint: Median overall survival (OS). 
Secondary endpoints: Overall Survival at 6, 9, and 12 months (OS6mo, OS9mo, OS12mo), 
Median Progression Free Survival (PFS), Progression Free Survival at 4, 6, 9, and 12 
months (PFS4mo, PFS6mo, PFS9mo, PFS12mo), Objective tumor response measured by RANO 
(Response Assessment in Neuro-Oncology Criteria), Time to recurrence.  Other outcomes 
measured will be Health-Related Quality of Life (HRQOL) as an outcome measure using a 
self-reported, and validated questionnaire, addressing physical, psychological, emotional, 
and social issues. 


 
 
 
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Procedures to be performed: 
This clinical study utilizes sample specimens obtained during: 
1. 
The routine surgical resection of already diagnosed recurrent cancer 
Standard biopsy procedures or resection of tumors will be conducted by the surgeons who 
routinely perform these procedures. The current study will utilize only sample specimens 
obtained by established procedures that patients have to routinely undergo for the treatment 
of his/her recurrent cancer; there is no additional risk to the patient. Tissue for this study will 
only be obtained when it is assured that there is adequate tissue for routine histologic 
analysis.  At no time will tissue be obtained solely for the purpose of carrying out the 
chemo-sensitivity assay. 
After its removal, the biopsy or surgical specimen will be placed in a container with 
transportation medium. The container will be labeled and then shipped to the ChemoID 
laboratory at the Translational Genomics Research Institute (TGRI) in Cabell Huntington 
Hospital. ChemoID assay is performed by well-trained medical technologists in a Clinical 
Laboratory Improvement Amendments (CLIA) certified facility under the Centers for 
Medicare & Medicaid Services (CMS) guidelines. The performance characteristics of the 
ChemoID assay in terms of its accuracy, precision, analytical sensitivity and analytical 
specificity are certified by both CLIA and College of American Pathologists (CAP). The 
clinical utility of the assay as performed is documented in several peer-reviewed 
publications and ASCO abstracts (1-7). 
 
 


 
 
 
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Study Title 
Standard chemotherapy versus chemotherapy chosen by 
cancer stem cell chemosensitivity testing in the management of 
patients with recurrent Glioblastoma Multiforme (GBM) and 
recurrent WHO Grade III Glioma. 
Funder 
ChemoID 
Clinical Phase 
III 
Study Rationale 
At recurrence, a minority of patients is eligible for second surgery or 
re-irradiation, based on appropriate patient selection.   
There is no standard of care for the chemotherapy portion of their 
treatment, and the management of recurrent glioblastoma and 
recurrent WHO III Glioma continues to be a moving target as new 
therapeutic principles enrich the standards of care for newly 
diagnosed disease.  Recurrent or progressive glioblastoma is most 
commonly treated with nitrosoureas, temozolomide, CPT-11, 
bevacizumab, and/or combinations of these agents. 
The ability to individualize therapy by providing the treating 
physician with drug response information on a panel of approved 
drugs should aid in the selection of effective therapy for individual 
patients, thus resulting in improved outcomes.  
ChemoID assay is a high-complex CLIA and CAP certified 
chemosensitivity test that uses a patient’s live tumor cells to indicate 
which chemotherapy agent (or "combinations") will kill not only the 
bulk of the cancer tumor but also the cancer stem cells (CSCs).  
Because CSCs are very resistant to chemotherapy and radiation, 
empirical choice treatments often fail to choose drugs that act on 
CSCs, which are responsible for tumor recurrence. Targeting of 
CSCs alongside the bulk of other cancer cells is a new paradigm in 
cancer treatment. This constitutes an important advantage of 
ChemoID approach in the management of newly diagnosed glioma 
patients. 
We would like to determine the clinical validity of chemosensitivity 
tumor testing on the bulk tumor cells as well as cancer stem cells as 
a predictor of clinical response in the management of recurrent 
glioblastoma. 
 
Study Objective(s) 
The primary objective of this study is to compare patients with 
recurrent GBM and recurrent WHO grade III glioma receiving 
standard of care versus chemosensitivity assay-guided 
chemotherapy for the chemotherapy portion of their therapy: 
Median Overall Survival (OS). 
 


 
 
 
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xiii
 
The secondary objectives of this study are to compare: 
• Overall Survival at 6, 9, and 12 months (OS6mo, OS9mo, 
OS12mo) 
• Median Progression Free Survival (PFS)  
• Progression Free Survival at 4, 6, 9, and 12 months (PFS4mo, 
PFS6mo, PFS9mo, PFS12mo) 
• Objective tumor response measured by RANO (Response 
Assessment in Neuro-Oncology Criteria) 
• Time to recurrence  
• Health-Related Quality of Life (HRQOL)  
Test Article(s) 
(If Applicable) 
ChemoID assay is a high-complex CLIA and CAP certified drug 
response assay that uses a patient’s live tumor cells to indicate 
which chemotherapy agent (or "combinations") will kill not only the 
bulk of the cancer tumor but also the cancer stem cells (CSCs).   
CSCs are a small sub-population of cancer cells within a patient’s 
tumor that are very resistant to chemotherapy and radiation and that 
are responsible of cancer recurrence.  Empirical choice treatments 
often fail to choose drugs that act on CSCs. This may help to 
explain why early tumor shrinkage is often poorly predictive of 
overall survival. While conventional therapies kill the bulk of non-
stem cancer cells, resulting in tumor shrinkage, CSCs may remain 
viable and later reestablish the tumor, leading to relapse. A potential 
new approach to address this is the targeting of both CSCs and bulk 
tumor cells with most effective chemotherapy choices for improved 
clinical outcome. ChemoID assay serves as a clinically actionable 
tool for oncologists by measuring percent of cell kill of CSCs and 
bulk tumor cells by direct visualization and quantification of cell 
death following exposure to FDA approved chemotherapy agents. 
When ordering the assay, a physician selects each of the multiple 
treatments under consideration for a given patient for inclusion in 
the assay.  
Study Design 
 
The proposed study is a parallel group randomized controlled 
clinical trial. 
Upon obtaining informed consent, participants with recurrent GBM 
who can be surgically resected will be registered to the trial and 
have tumor biopsy samples undergo CSCs chemosensitivity testing 
with multiple FDA approved chemotherapeutic agents. 
Then participants will be randomized to either:  
(ARM 1) Standard of care chemotherapy chosen by the physician or 


 
 
 
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xiv
(ARM 2) ChemoID-guided therapy. 
Subject Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria 
 
1. 
Men and Women and members of all ethnic groups who are 
at least 18 years old at the time of enrollment are eligible for 
this trial; 
2. 
Informed consent obtained and signed; Informed consent 
obtained and signed; Informed consent may be obtained 
from a legal authorized representative when the person is not 
competent, incapacitated, or otherwise unable to make an 
informed judgment 
3. 
Willing and able to commit to study procedures including 
long-term follow-up visit(s) on or off the study protocol; 
4. 
 
 
 
   
5. 
In all cases, the diagnosis must be confirmed by a 
pathologist.  
6. 
Recurrent surgically resectable tumor and/or biopsy; 
7. 
Participants who have undergone surgical resection should 
have received an MRI or a scan after surgery in order to 
visualize residual tumor. If not, the operative report must be 
available; 
8. 
Prior to surgery there was imaging evidence of measurable 
progressive disease (PD); 
9. 
Re-radiation, if indicated, should occur at least 2 weeks after 
surgery and/or biopsy once the wound has healed well 
without any drainage or cellulitis; 
10. 
Estimated survival of at least 3 months; 
11. 
Hgb > 9 gm; absolute neutrophil count (ANC) > 1500/µl; 
platelets > 100,000; Creatinine < 1.5 times the upper limit of 
laboratory normal value; Bilirubin < 2 times the upper limit 
of laboratory normal value with the exception of Gilbert’s 
syndrome; serum glutamate pyruvate transaminase (SGPT) 
or serum glutamate oxaloacetate transaminase (SGOT) < 3 
times the upper limit of laboratory normal value; 
12. 
Chemotherapy must start within 8 weeks of tumor resection 
or biopsy; 
13. 
Bevacizumab (Avastin) is allowed. If indicated it should be 
initiated at least 4 weeks post craniotomy or biopsy if the 
wound has healed well without any drainage or cellulitis; 
14. 
The use of herbal preparation or 
Histopathologically confirmed 2016 WHO grade III 
recurrent glioma, and grade IV recurrent glioblastoma 
(GBM), inclusive of Gliosarcoma.


 
 
 
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xv 
tetrahydrocannabinol/cannabidiol is strongly discouraged, 
but not contraindicated; 
 
Exclusion Criteria 
1. Subjects with newly diagnosed GBM 
2. Pregnant women or nursing mothers cannot participate in the 
study. Women of childbearing age must have a negative 
pregnancy test prior to study entry. Women of childbearing 
potential must practice medically approved contraceptive 
precautions; 
3. 
Abnormal hematological results at inclusion with: 
     - Neutrophils < 1,500/mm3 
     - Blood-platelets < 100,000/mm3 
4. Severe or chronic renal insufficiency (creatinine clearance ≤ 30 
ml/min); 
5. Patient unable to follow procedures, visits, examinations 
described in the study; 
6. Any usual formal indication against imaging examinations 
(important claustrophobia, pacemaker); 
7. History of another malignancy in the previous 2 years, with a 
disease-free interval of < 2 years. Patients with prior history 
of in situ cancer or basal or squamous cell skin cancer, any 
time prior to screening, are eligible. 
8. OPTUNE device is not permitted in the study; 
9. Patients cannot participate to any clinical trials utilizing a liquid 
biomarker or imaging studies that impact the overall 
survival. 
 
Number Of Subjects  
 
Total Number of Subjects (150, or until the primary endpoint is 
met) 
Total Number of Sites (13) 
Study Duration 
Each subject’s participation will last up to 3 years 
The entire study is expected to last 3-5 years 
Study Phases 
 
1- Screening 
 
 
 
2- Study Treatment 
 
3 phases 
 
1) Screening for eligibility and obtaining consent 
 
2) Resection or  biopsy of tumor and Randomization study of 
Standard-of-Care chemotherapy vs. ChemoID-guided treatment in 
recurrent GBM patients 
 
3) Study visits with clinical assessment and brain MRI or CT scan 


 
 
 
WIRB 20172720 
 
 
 
 
 
 
xvi
 
3- Follow-Up 
   
with contrast.  Clinical lab, visit, and MRI or CT imaging as per 
standard of care. HRQoL. 
 
Efficacy Evaluations 
Primary outcome: Median Overall Survival (OS). 
Secondary outcomes: Overall Survival at 6, 9, and 12 months 
(OS6mo, OS9mo, OS12mo), Median Progression Free Survival (PFS), 
Progression Free Survival at 4, 6, 9, and 12 months (PFS4mo, 
PFS6mo, PFS9mo, PFS12mo), objective tumor response measured by 
RANO (Response Assessment in Neuro-Oncology Criteria) (8) on 
brain MRI or CT scans with contrast), time to recurrence, and 
Health-Related Quality of Life. 
 
Pharmacokinetic 
Evaluations 
(N/A) 
Safety Evaluations 
Chemotherapies used are FDA approved to treat this disease and are 
part of standard of care 
All Statistical And 
Analytic Plan 
The primary endpoint of improved median overall survival will be 
examined using logistic regression under an intention to treat 
analysis. 
DATA AND SAFETY 
MONITORING PLAN 
A DSMB will be responsible to monitor data quality management 
and ongoing assessment of safety 
 


 
xvii  
WIRB 20172720 
 
 
 
 
 
 
TABLE 1: SCHEDULE OF STUDY PROCEDURES  
Study Phase 
Screening 
Treatment/ 
Intervention 
Follow-up visits 
Visit Number 
 
1 
2 
3 
4 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 12 
13-24 
Informed 
Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs: BP, HR, 
RR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory 
Evaluation (if collected 
as per standard of care) 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
(13, 15, 
17, 19, 
21, 23) 
X 
Brain MRI or CT scan 
with or w/o contrast (if 
collected as per 
standard of care) 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Assessment 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
HRQOL assessment 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
xviii  
WIRB 20172720 
 
 
 
 
 
 
 
Study Phase (contd.) 
Screening 
Treatment/ 
Intervention 
Follow-up visits 
Visit Number (contd.) 
 
1 
2 
3 
4 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 12 
13-24 
Scheduling for Surgical 
removal and Tumor 
Biopsy for Diagnosis, 
and ChemoID testing 
(at the same time)  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization of 
patients to receive 
either physician choice 
chemotherapy 
or 
ChemoID-guided 
therapy 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Pathology 
report (MGMT, IDH-1) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of ChemoID 
drug response assay for 
Arm 2 participants 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense 
Chemotherapy Drug as 
per assigned ARM 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Compliance 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Assessment 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
.


 
page xix 
WIRB 20172720  
 
 
 
STUDY DIAGRAM 
 
  
 
 
 
 


 
 
WIRB 20172720 
 
 
 
1
1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 Introduction 
Recurrent glioblastoma WHO Grade IV patients have poor prognosis.   
At recurrence, only a fraction of patients is eligible for second surgery or reirradiation, based 
on appropriate patient selection.  Additionally, for the chemotherapy portion of their 
treatment, there is no consensus on the management of recurrent glioblastoma as new 
therapeutic principles enrich the standards of care for newly diagnosed disease.   
Although, no investigations have been conducted to define effective strategies against 
recurrence that occurs in most patients following combined radiotherapy/temozolomide 
regimens, treatment of recurrent or progressive glioblastoma with nitrosoureas, 
temozolomide, CPT-11, bevacizumab, and/or combinations of these agents are most 
commonly used.  
Following is a Kaplan-Meier plot of survival curve comparing progression free survival 
(Panel A) and overall survival (Panel B) of GBM recurrent patients treated with 
Bevacizumab (BV) alone or with Bevacizumab + CPT11 (BV+CPT11) demonstrating that 
the median PFS times were 4.2 months (95.0% CI, 2.9 to 5.8 months) for the BV group and 
5.6 months (95.0% CI, 4.4 to 6.2 months) for the BV + CPT-11 group (Panel A), and that 
the median OS times from the time of random assignment were 9.2 months (95.0% CI, 8.2 
to 10.7 months) for the BV group and 8.7 months (95.0% CI, 7.8 to 10.9 months) for the BV 
+ CPT-11 group (Panel B) (9).  
 
From: Friedman H.S. et al. Bevacizumab Alone and in Combination With Irinotecan in 
Recurrent Glioblastoma.  J. Clin Oncol 27:4733-4740, 2009. 


 
 
WIRB 20172720 
 
 
 
2
The ChemoID drug response assay is a CLIA certified and CAP accredited functional test 
that uses patient’s live tumor cells to indicate which chemotherapy agent (or combinations) 
will kill not only cancer cells, but more importantly the cancer stem cells (CSCs) that are 
known to cause cancer to recur.  
The rationale for this study is that current treatments often fail to choose drugs that act on 
CSCs, which are responsible for therapy resistance and cancer progression.  Recurrent 
glioblastoma remains a largely unmet medical need, which highlights the need for effective 
therapies.  Targeting of CSCs alongside the bulk of other cancer cells is a new paradigm in 
cancer treatment.  This constitutes an important advantage of ChemoID approach over other 
assays available. By testing multiple chemotherapies on a patient's tumor cells before 
clinically treating a cancer patient, ChemoID drug response assay may enable faster reaction 
time to administer the optimum selection of chemotherapy drug(s), increased patient 
survival, and lower treatment costs by eliminating unnecessary chemotherapies, and 
decreased levels of toxicity. 
ChemoID drug response assay in a clinical study of 42 consecutively treated patients 
showed statistically significant improved response rate (2.2-fold increase) in patients who 
were given assay-indicated chemotherapy. Results from this study indicate that a drug 
response assay that targets CSCs may be a very useful tool for optimizing treatment 
selection when first-line therapy fails and when there are multiple clinically acceptable and 
equivalent treatments available. 
Additionally, the assay has been prospectively used in 30 additional GBM patients showing 
proof of assay-directed therapy to effectively determine chemotherapy regimens that 
improved clinical outcomes. 
 
 


 
 
WIRB 20172720 
 
 
 
3
1.2 Name and Description of Investigational Product or Intervention 
ChemoID is a functional drug response assay performed in a clinical laboratory at Cabell 
Huntington Hospital.  The performance characteristics of the ChemoID assay in terms of its 
accuracy, precision, analytical sensitivity and analytical specificity are certified by CLIA 
(Clinical Laboratory Improvement Amendments) and CAP (College of American 
Pathologists).  The test is performed under the Medicare & Medicaid Services (CMS) 
guidelines as a Laboratory Developed Test (LDT).  The assay uses patient’s live tumor cells 
to indicate which chemotherapy agent (or combinations) will kill not only cancer cells, but 
also and more importantly, the cancer stem cells (CSCs) that are known to cause cancer to 
recur.  
Sample of a ChemoID Assay Report from a GBM patient 
 
 
 
 
 
 
 
 
 
 
 
1.3 Findings from Non-Clinical and Clinical Studies  
1.3.1 Clinical Studies 
A prospective clinical investigation was conducted using the ChemoID assay to measure the 
sensitivity and resistance of CSCs and bulk of tumor cells cultured from 42 GBM clinical 
samples challenged with several chemotherapy agents, which were correlated to the clinical 
response of the treated patients, independently of other biomarkers. Patients were all treated 
with standard-of-care TMZ plus radiation with or without maximal surgery, depending on 
the status of the disease. Patients were prospectively monitored for tumor response, time to 
recurrence, progression-free survival (PFS), and overall survival (OS). Odds ratio (OR) 
associations of 12-month recurrence, PFS, and OS outcomes were estimated for CSC, bulk 
tumor, and combined assay responses for the standard-of-care TMZ treatment; 
sensitivities/specificities, areas under the curve (AUCs), and risk reclassification 
components were examined (6, 7).  


 
 
WIRB 20172720 
 
 
 
4
Clinical Study Results: Median follow-up was 8 months (range 3-49 months). For every 
5% increase in in vitro CSC cell kill by TMZ, 12-month patient response (non-recurrence of 
cancer) increased two-fold, OR = 2.2 (P = .016). Similar but somewhat less supported 
associations with the bulk tumor test were seen, OR = 2.75 (P = .07) for each 5% bulk tumor 
cell kill by TMZ. Combining CSC and bulk tumor assay results in a single model yielded a 
statistically supported CSC association, OR = 2.36 (P = .036), but a much attenuated 
remaining bulk tumor association, OR = 1.46 (P = .472). AUCs and [sensitivity/specificity] 
at optimal outpoints (N40% CSC cell kill and N55% bulk tumor cell kill) were AUC = 0.989 
[sensitivity = 100/specificity = 97], 0.972 [100/89], and 0.989 [100/97] for the CSC only, 
bulk tumor only, and combined models, respectively. Risk categorization of patients was 
improved by 11% when using the CSC test in conjunction with the bulk test (risk 
reclassification nonevent net reclassification improvement [NRI] and overall NRI = 0.111, P 
= .030). Median recurrence time was 20 months for patients with a positive (N40% cell kill) 
CSC test versus only 3 months for those with a negative CSC test, whereas median 
recurrence time was 13 months versus 4 months for patients with a positive (N55% cell kill) 
bulk test versus negative. Similar favorable results for the CSC test were observed for PFS 
and OS outcomes.  
Comparison of most sensitive drug from a panel of various chemotherapies vs. Temodar   
 
 
 
 
 
 
 
Results across a panel of 14 potential other treatments indicated that 34/41 (83%) potentially 
more optimal alternative therapies may have been chosen using CSC results, whereas 27/41 
(66%) alternative therapies may have been chosen using bulk tumor results.  
A pyramid plot of percent cell kill for the most cytotoxic drug and TMZ comparing CSC 
and bulk tests for each patient is illustrated above. Optimal therapies with the highest cell 
kill are shown in light colors and TMZ cell kill is shown in dark colors with each row of the 
pyramid corresponding to results for a single patient. When the light bar is longer than the 
dark bar, a potentially more optimal therapy than TMZ is identified. CSC results outlined in 
red show patients whose CSC test identified an optimal therapy that was different than the 
optimal therapy identified by the bulk test, 17/41 patients, 42% (95%CI 26-57%) p<0.001.  
 
 


 
 
WIRB 20172720 
 
 
 
5
1.4 Selection of Drugs and Dosages 
List of Current Chemotherapeutic Agents and suggested Combinations on the ChemoID® GBM 
Drug Panel 
  
Single Drug 
Dose 
1 
Carboplatin 
350 mg/m2 or 4 AUC 
2 
Irinotecan 
125 mg/m2 
3 
Etoposide 
50 mg/m2 
4 
BCNU 
100 mg/m2 
5 
CCNU 
100 mg/m2 
6 
Temozolomide 
150-200 mg/m2 
7 
Procarbazine 
60 mg/m2 
8 
Vincristine 
1.4 mg/m2 
9 
Imatinib 
400 mg 
  
Drug Combination 
Dose 
1 
Procarbazine 
60 mg/m2 
  
CCNU 
100 mg/m2 
  
Vincristine 
1.4 mg/m2 
2 
Carboplatin 
350 mg/m2 or 4 AUC 
  
Irinotecan 
125 mg/m2 
3 
Carboplatin 
350 mg/m2 or 4 AUC 
  
Etoposide 
50 mg/m2 
4 
Temozolomide 
50 mg/m2 
  
Etoposide 
50 mg/m2 
5 
Temozolomide 
50 mg/m2 
  
Imatinib 
200 mg 
 
Patients should receive treatment per standard practice and may continue on 
treatment until progression per investigator discretion if having continued response 
and/or clinical benefit.  The number of cycles of therapy should be administered as 
clinically appropriate, although it is suggested that patients should receive at least 4 
cycles of therapy.   
 
1.5 Relevant Literature and Data 
The following figure illustrates the relationship between the TMZ CSC assay results 


 
 
WIRB 20172720 
 
 
 
6
(%-cell kill on the y -axis) and TMZ bulk tumor assay results (%-cell kill on the x -axis) 
characterized by 12-month recurrence outcomes, with solid circles representing treatment 
responders (patients who did not manifest a recurrence at 12 months) and open circles 
representing patients manifesting recurrence within 12 months from treatment (6, 7). 
Referent lines are drawn at the optimal thresholds from the logistic regression models (40% 
for CSC, 55% for bulk tumor). In the upper-right quadrant are patients with high TMZ cell 
kill for both CSC and bulk tumor assays where 5/41 (12%) had prolonged tumor response 
and only 1 (2.4%) was recurrent. In the lower-left quadrant are patients with low TMZ cell 
kill for both CSC and bulk tumor assays; all 31 (76%) recurred within 12 months from 
treatment. Finally, the lower-right quadrant shows patients whose TMZ bulk tumor assay 
showed a high cell kill (> 55%) but whose TMZ CSC assay showed a low cell kill (< 40%); 
all 4/41 (10%) recurred within 12 months.  
When the CSC assay results were considered separately, every 5% increase in TMZ 
CSC %-cell kill was associated with a significant two-fold increase in 12-month patient 
response (non recurrence of cancer), OR = 2.2 (95% CI 1.16-4.17), P  = .016.  
TMZ bulk tumor %-cell kill was similarly associated but with less statistical support, OR = 
2.8 (0.93-8.06) P  = .066 for each 5% increase. 
When the CSC and bulk test results were analyzed together in a single, multivariate 
model, the CSC test again showed a statistically supported OR of 2.36 (1.06-5.25) P  = .036, 
whereas the bulk of tumor test association fell to OR = 1.46 (0.52-4.08) P  = .472. 
 
 
 
 
 
 
 
 
 
 
ChemoID assay areas under the curve were high for all three models: 
Quadrant diagram of the relationship between TMZ CSC assay results (%-cell kill on the y-
axis) and TMZ bulk tumor assay results (%-cell kill on the x-axis) characterized by 12-month 
recurrence outcomes. Solid circles represent treatment responders (patients who did not 
manifest a recurrence at 12 months), and open circles represent patients manifesting 
recurrence within 12 months from treatment. Optimal threshold referent lines from the 
logistic regression models (40% for CSC, 55% for bulk tumor) are illustrated. 


 
 
WIRB 20172720 
 
 
 
7
AUC = 0.989, 0.972, and 0.989 for the separate CSC, bulk tumor, and combined model, 
respectively.  Related optimal thresholds for the assays were 40% CSC cell kill and 55% 
bulk tumor cell kill by TMZ which then provided sensitivities/specificities of 100/97, 
100/89, and 100/97 for the three models, respectively. Both the CSC assay and the bulk 
tumor assay performed well in these models and in related secondary models for OS & PFS, 
with the CSC assay showing slightly improved results over the bulk tumor results 
throughout. 
The following figure shows Kaplan-Meyer plots of time to recurrence stratified by 
ChemoID test results from the clinical study using the optimal TMZ thresholds (40% cell 
kill for CSC and 55% cell kill for bulk tumor). Patients with positive ChemoID CSC tests 
(>40% cell kill) had longer median times to recurrence (20 months) than those with negative 
CSC tests (3 months). Patients with positive bulk tumor tests (>55% cell kill) had longer 
median times to recurrence (13 months) than those with negative bulk tumor tests (4 
months), but the separation was not as great.  
 
 
 
 
 
1.6 Compliance Statement 
This study will be conducted in full accordance of all applicable Research Policies and 
Procedures of the investigators institution and all applicable Federal and state laws and 
regulations including 45 CFR 46, 21 CFR Parts 50, 54, 56, and the Good Clinical Practice: 
Consolidated Guideline approved by the International Conference on Harmonization (ICH). 
All episodes of noncompliance will be documented. 
Kaplan-Meier plots of tumor recurrence across the study period. Survival (tumor non 
recurrence) is shown stratified by dichotomized test results (TMZ optimal thresholds of 
CSCs> 40% and bulk test >55%); P for both <.001 in Cox proportional hazard models. 


 
 
WIRB 20172720 
 
 
 
8
The investigators will perform the study in accordance with this protocol, will obtain 
consent and assent, and will report unanticipated problems involving risks to subjects or 
others in accordance with the ASRI-WPAHS IRB Policies IRB Policies and Procedures and 
all federal requirements. Collection, recording, and reporting of data will be accurate and 
will ensure the privacy, health, and welfare of research subjects during and after the study.  
 
 


 
 
WIRB 20172720 
 
 
 
9
2 
STUDY OBJECTIVES 
The purpose of the study is to determine the validity of chemosensitivity (ChemoID) tumor 
testing on cancer stem cells as a predictor of clinical response in recurrent glioblastoma and 
recurrent WHO grade III glioma 
2.1 Primary Objective (or Aim) 
The primary objective of this study is to compare patients with recurrent GBM and recurrent 
WHO grade III glioma who receive the standard of care versus chemosensitivity assay 
directed chemotherapy for the chemotherapy portion of their therapy: 
• Median Overall Survival (OS). 
2.2 Secondary Objectives (or Aims) 
The secondary objectives of this study are to compare: 
• Overall Survival at 6, 9 and 12 months (OS6mo, OS9mo, OS12mo) 
• Median Progression Free Survival (PFS)  
• Progression Free Survival at 4, 6, 9, and 12 months (PFS4mo, PFS6mo, PFS9mo, 
PFS12mo) 
• Objective tumor response measured by RANO (Response Assessment in Neuro-
Oncology Criteria) 
• Time to recurrence 
• Health-Related Quality of Life (HRQOL)  
 
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
This study is designed as a parallel group randomized controlled clinical trial to 
determine if recurrent GBM patients treated with drugs predicted by ChemoID assay will 
have better outcomes than patients treated with standard of care. 
 
3.1.1 Screening Phase 
 
 
 
 
 
 
 
 
 
 
Under standard-of-care, patients will be screened using brain MRI with gadolinium contrast, 
which will be followed by tumor resection and biopsy procedure. 
 
3.1.2 Study Treatment Phase 1 (start of the study intervention) 
Under standard-of-care, eligible participants will undergo surgical resection and/or biopsy.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Eligible patients with recurrent GBM and recurrent 2016 WHO grade III glioma will  be 
identified using the protocol inclusion and exclusion criteria and will be consented to the 
trial.


 
 
WIRB 20172720 
 
 
 
10 
Fresh tissue tumor biopsies will be sent to Pathology to confirm diagnosis of GBM or 
recurrent WHO grade III glioma, the methylation status of the MGMT gene promoter, and a 
portion of the fresh biopsy will be sent to the ChemoID lab at the Cabell Huntington 
Hospital, WV to perform the drug response assay.   
Shipment of samples to the ChemoID lab are performed using a secure shipping container 
for biological samples and the FEDEX carrier using standardized procedure under CLIA and 
CAP regulations. 
Participants with recurrent GBM will be registered to the trial. 
Informed consent will be obtained prior to any study related procedures being performed, 
including discontinuation of current therapy.   
An MRI (or CT if patient is unable to have an MRI performed) of the brain with and without 
contrast will have been performed within 14 days of the screening visit.  
Blood samples will be drawn as per standard-of-care and will be used to confirm eligibility 
based on clinical laboratory parameters.  Females will have a urine or serum pregnancy test. 
 
3.1.3 Study Treatment Phase 2  
All recurrent GBM and recurrent WHO grade III glioma participants registered to the trial 
will be randomized using a computer-generated process and placed in the appropriate study 
arm. 
 
3.1.4 Study Treatment Phase 3  
Participants will be treated according to the randomly assigned study arm: 
(ARM 1) standard of care chemotherapy chosen by the physician 
or 
(ARM 2) ChemoID-guided therapy. 
 
3.1.5 Follow-up Phase 
Participants will be followed according to standard-of-care intervals by neurologic and 
neurosurgical clinical assessments preferably with brain MRI scans pre- and post 
intravenous gadolinium contrast unless the patient has a contraindication to gadolinium 
contrast then non-contrast brain MRI will be obtained and or CT-scans of the brain pre and 
post intravenous contrast or without contrast if the patient has a contraindication to CT IV 
contrast such as severe allergy and/or renal dysfunction. 


 
 
WIRB 20172720 
 
 
 
11 
Response to chemotherapy will be evaluated according to the 2D Response Assessment in 
Neuro-Oncology (RANO) criteria, in which in addition to contrast enhancement, tumor 
extension on T2- and fluid-attenuated inversion recovery (FLAIR)-weighted MRI are 
evaluated (8). Furthermore, an assessment of neurological function and corticosteroid use is 
included. 
The follow-up phase will continue for up to 3 years or death.  At 6 and 12 months after Visit 
24 there will be a phone call to assess survival status.  
 
3.2 Allocation to Treatment Groups and Blinding 
Participants will be randomized using a statistical random number generator in 
RedCap.   
Participants will be treated according to the assigned study arm. 
 
3.3 Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Study Participation 
The study duration per subject will be up to 3 years or until death, with up to 3 days 
screening, up to 1 day Phase 1, up to 1 day Phase 2, and 1 day Phase 3, and 26 days follow-
up.  Participants will be followed according to standard-of-care intervals by neurologic and 
neurosurgical clinical assessments as detailed in Table 1: schedule of study procedures. 
Patient will be followed for overall survival on or off the clinical trial. 
 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The settings for this study are: 
1. Allegheny Health Network, Pittsburgh, PA 
2. University of Mississippi Medical Center, Jackson, MS 
3. University of Cincinnati, Brain Tumor Center, Cincinnati, OH 
4. Penn State Hershey Neuroscience Institute, Hershey, PA 
5. The University of Toledo, Eleanor N. Dana Cancer Center, Toledo, OH 
6. Charleston Area Medical Center, Charleston, WV 
7. Maine Medical Center Institute, Scarborough, ME 
8. Providence Brain and Spine Institute, Portland, OR 
9. Thomas Jefferson University Hospital, Philadelphia, PA 
10. St. Luke’s University Health Network, Bethlehem, PA 
11. Louisiana State University Health Sciences Center, New Orleans, LA 
12. Kaiser Permanente, Los Angeles, CA 
13. University of Southern California, Los Angeles, CA 
 
 


 
 
WIRB 20172720 
 
 
 
12 
The total number of evaluable subjects projected is N=150 (see statistical section below).  
 
3.4 Study Population 
3.4.1 Inclusion Criteria 
1) Men and Women and members of all ethnic groups who are at least 18 years old at 
the time of enrollment are eligible for this trial; 
2) Informed consent obtained and signed; Informed consent may be obtained from a 
legal authorized representative when the person is not competent, incapacitated, or 
otherwise unable to make an informed judgment. 
3) Willing and able to commit to study procedures including long-term follow-up 
visit(s) on or off the study protocol; 
 
 
 
 
5) In all cases, the diagnosis must be confirmed by a pathologist.  
6) Recurrent surgically resectable tumor and or biopsy; 
7) Participants who have undergone surgical resection should have received an MRI or 
a scan after surgery in order to visualize residual tumor. If not, the operative report 
must be available; 
8) Prior to surgery there was imaging evidence of measurable progressive disease (PD); 
9) Re-radiation, if indicated, should occur at least 2 weeks after surgery and/or biopsy, 
once the wound has healed well without any drainage or cellulitis; 
10) Estimated survival of at least 3 months; 
11) Hgb > 9 gm; absolute neutrophil count (ANC) > 1500/ul; platelets > 100,000; 
Creatinine < 1.5 times the upper limit of laboratory normal value; Bilirubin < 2 times 
the upper limit of laboratory normal value with the exception of Gilbert’s syndrome; 
serum glutamate pyruvate transaminase (SGPT) or serum glutamate oxaloacetate 
transaminase (SGOT) < 3 times the upper limit of laboratory normal value; 
12) Chemotherapy must start within 8 weeks of tumor resection or biopsy; 
13) Bevacizumab (Avastin) is allowed. If indicated, it should be initiated at least 4 weeks 
post craniotomy or biopsy if the wound has healed well without any drainage or 
cellulitis; 
14) The use of herbal preparation or tetrahydrocannabinol/cannabidiol is strongly 
discouraged, but not contraindicated; 
 
3.4.2 Exclusion Criteria 
1) Subjects with newly diagnosed GBM 
2) Pregnant women or nursing mothers cannot participate in the study. Women of 
childbearing age must have a negative pregnancy test prior to study entry. Women of 
childbearing potential must practice medically approved contraceptive precautions; 
3) Abnormal hematological results at inclusion with: 
4) Histopathologically confirmed 2016 WHO grade III recurrent glioma,
 
and grade IV recurrent glioblastoma (GBM), inclusive of Gliosarcoma;


 
 
WIRB 20172720 
 
 
 
13 
a. Neutrophils < 1,500/mm3 
b. Blood-platelets < 100,000/mm3 
4) Severe or chronic renal insufficiency (creatinine clearance ≤ 30 ml/min); 
5) Patient unable to follow procedures, visits, examinations described in the study; 
6) Any usual formal indication against imaging examinations (important 
claustrophobia, pacemaker); 
7) History of another malignancy in the previous 2 years, with a disease-free interval <2 
years. Patients with prior history of in situ cancer or basal or squamous cell skin 
cancer, any time prior to screening, are eligible. 
8) OPTUNE device is not permitted in the study; 
9) Patients cannot participate to any clinical trials utilizing a liquid biomarker or 
imaging studies that impact the overall survival. 
 
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations 
of these criteria must be reported in accordance with IRB Policies and Procedures.  
 
4 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE 
4.1 Treatment plan 
Participants with recurrent GBM and recurrent WHO grade III glioma will be registered to 
the trial and have tumor biopsy samples undergo CSCs chemosensitivity testing with 
multiple FDA approved chemotherapeutic agents. 
Participants will be randomized to a standard treatment arm (Arm 1) with chemotherapy 
chosen by the Physician from the provided list or to a study arm (Arm 2) of FDA-approved 
drugs selected by the ChemoID drug response assay. 
Routine clinical assessments including history, physical exam, and lab assessments prior 
to treatment with chemotherapy should be performed based on standard of 
care (i.e. assessment prior to Day 1 of chemotherapy cycle) and as often as deemed 
necessary per treating physician discretion. Reporting of these routine clinical assessments is 
not necessary unless there are delays in treatment or dose modifications.  These visits should 
be recorded as an Unscheduled Visit. 
 
4.2 Duration of therapy 
Participants enrolled to the standard of care chemotherapy or the ChemoID arms will 
continue treatment until unacceptable toxicity, hospice or death, or consent withdrawal.  
In Arm 1 - the patient should continue therapy until unacceptable toxicity, hospice or death, 
or consent withdrawal. At every progression confirmed by RANO criteria, the treatment 
plan will change as per the physician choice.   


 
 
WIRB 20172720 
 
 
 
14 
In Arm 2 - the patient should continue therapy until unacceptable toxicity, hospice or death, 
or consent withdrawal. At every progression confirmed by RANO criteria, the treatment 
plan will change as per as per the ChemoID assay.  
Alternatively: Arm 1 and 2 -: The number of cycles will be left up to the treating physician’s 
discretion. However, patients should receive a minimum of 4 cycles of therapy and ideally 
treated until unacceptable toxicity, hospice or death, or consent withdrawal. 
At the time of unacceptable toxicity or progression with the chemotherapy chosen from the 
ChemoID assay, treatment can be switched to ChemoID-based next chemotherapeutic agent 
or combination in Arm 2.  
Bevacizumab is allowed in the clinical trial. If indicated it should be initiated at least 4 
weeks post craniotomy or biopsy if the wound has healed well without any drainage or 
cellulitis. Bevacizumab is not expected to improve overall survival. On Bevacizumab the 
response to treatment and pseudo-response will be evaluated by each institution current 
radiographic assessments guidelines. 
Re-radiation is allowed at any point at least 2 weeks postsurgical procedure, if the wound 
has healed well without any drainage or cellulitis 
 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following 
criteria applies:  
 
Hospice or patients’ death 
 
Intercurrent illness that prevents further administration of treatment,  
 
Unacceptable adverse event(s) 
 
Patient decides to withdraw consent for participation in 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.  
 
CT scan or MRI will be performed as standard of care for the entire time 
patients are in the trial, and at any other time if clinically indicated based on 
symptoms or physical signs suggestive of progressive disease.   Imaging assessments 
will be discontinued once patient is off of the clinical trial, hospice or death. Patient 
will be followed for the overall survival on or off the clinical trial.  
 
4.3 Treatment window  
A patient will be permitted to have a new cycle of chemotherapy delayed up to 
7 days (without this being considered to be a protocol violation) for major life events 
(e.g., serious illness in a family member, major holiday, vacation which is unable to 
be scheduled).    


 
 
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It will be acceptable for individual chemotherapy doses to be delivered within a “24 
hour window before and after the protocol-defined date” for “Day 1” treatment of weekly 
treatment or 21- or 28- day cycles.   If the treatment due date is a Friday, and the patient 
cannot be treated on that Friday, then the window for treatment would include the Thursday 
(1 day earlier than due) through Monday (day 3 past due).  
 
4.4 ARM 1 - Physicians Choice of chemotherapy regimens 
Patients randomized to the physician choice chemotherapy arm may be treated 
with one of the regimens specified in section 8.1 per investigator discretion.  Patients 
should receive treatment per standard practice and may continue on treatment until 
hospice or as per investigator discretion if having continued response (SD, PR or CR) 
and/or clinical benefit.  The number of cycles of therapy should be administered as 
clinically appropriate, although it is suggested that patients should receive at least 4 
cycles of therapy.   
 
4.5 ARM 2 – ChemoID Drug Response Assay chemotherapy regimens 
The physician will choose treatment regimen based on ChemoID drug response 
assay results on cancer stem cells (CSC) and bulk of tumor cells.   Ideally, the regimen 
with the highest percentage cell kill for cancer stem cells and bulk of tumor combined 
should be used, however the physician has the flexibility to choose the best regimen 
according to anticipated patient tolerability.  The regimens tested by the ChemoID 
drug response assay are the same as the one that can be chosen by the Physician for 
patients enrolled in Arm 1. 
The dosing of the chemotherapy can be modified as per physician discretion. At the time of 
progression with the first agent from ChemoID assay, treatment can be switched to 
ChemoID based next chemotherapeutic agent or combination. Bevacizumab is allowed in 
the clinical trial. If indicated it should be initiated at least 4 weeks post craniotomy or biopsy 
if the wound has healed well without any drainage or cellulitis. Bevacizumab is not expected 
to improve overall survival (10, 11). On Bevacizumab the response to treatment and pseudo-
response will be evaluated by each institution’s current radiographic assessments guidelines. 
Re-radiation is allowed at any point at least 2 weeks postsurgical procedure, if the wound 
has healed well without any drainage or cellulitis. 
 
 
 
4.6 Duration of Study  
Participants enrolled to the standard of care chemotherapy or the ChemoID arms will 
continue treatment until  hospice or death, unacceptable toxicity, or consent withdrawal.  
Patients will receive chemotherapy as per standard of care regimens.  The number of cycles 
will be per the investigator’s discretion.  After completion of chemotherapy, patients will 


 
 
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continue on active surveillance every month.  The patient may voluntarily withdraw from 
the study at any time. 
 
4.7 Follow-up after study treatment discontinuation  
Participants enrolled to the standard of care chemotherapy or the ChemoID arms will 
continue follow up until death or consent withdrawal.  
5 
STUDY PROCEDURES 
See Table 1 for the procedures and assessments to be performed during this phase of the 
study.  All screening visit tests and procedures will occur within 14 days of the signed 
informed consent (IC). No screening exams will take place until the patient is fully informed 
of the research and signs the informed consent. This visit may take place over more than one 
day. Any MRI or CT scans done under standard of care are acceptable to screen patients. 
 
5.1 Screening Visit 
See Table 1 for the procedures and assessments to be performed during this phase of the 
study. The Screening Phase will take place over a two-week period, and it may be split into 
two visits.  The Screening Visit will be performed by the study investigator to determine if 
the patient is eligible for the study. 
Following are the steps involved with this phase of the study: 
• Physical Exam and Clinical Assessment 
• Vital Signs 
• Height and Weight 
• Pregnancy test 
• Laboratory tests 
• Brain Imaging by MRI or CT scan preferentially with contrast 
• Medical Record Review 
• Prior/Concomitant Medications 
• Clinical Laboratory Evaluation 
• Review Inclusion/Exclusion criteria 
• Informed Consent 


 
 
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5.2 Enrollment Contingency Plans 
In order to take into account certain unexpected events that can disrupt the planned study 
schedule, enrolled participants who unexpectedly expire prior to surgery or who are 
otherwise withdraw from the study after the screening period but before surgery, may be 
replaced without limit. 
 
5.3 Study Treatment Phase 
See Table 1 for the procedures and assessments to be performed during this phase of the 
study.  Informed consent will be obtained prior to any study related procedures being 
performed, including discontinuation of current therapy.   
Participants with recurrent GBM will be registered to the trial.  An MRI (or CT if patient is 
unable to have an MRI performed) of the brain with and without contrast will have been 
performed within 14 days of the screening visit.  
Blood samples will be drawn as per standard-of-care and will be used to confirm eligibility 
based on clinical laboratory parameters.  Females will have a urine or serum pregnancy test. 
Under standard of care, eligible participants with recurrent GBM or grade III glioma will 
undergo surgical resection and biopsy.   Fresh tissue tumor biopsies will be sent to 
Pathology to confirm diagnosis of GBM, MGMT gene methylation status, IDH-1/2 status, 
and a portion of the fresh biopsy will be sent to the ChemoID lab at the Cabell Huntington 
Hospital, WV to perform the drug response assay.   
Shipment of samples to the ChemoID lab will be performed using a secure shipping 
container for biological samples and the FEDEX carrier using standardized procedure under 
CLIA and CAP regulations. 
All recurrent GBM participants registered to the trial will be randomized using a computer 
generated process and placed in the appropriate study arm. 
Participants will be treated according to the randomly assigned study arm: 
(ARM 1) standard of care chemotherapy chosen by the physician 
or 
(ARM 2) ChemoID-guided therapy. 
Drugs will be dispensed according to study arm. Drug compliance and adverse event 
assessment will be performed. 
Following are the steps involved with this phase of the study: 
 


 
 
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5.3.1 Visit 1 – pre-op visit 
• Physical Exam (conducted under standard of care) 
• Vital Signs (conducted under standard of care) 
• Under standard of care, any brain imaging by MRI or CT scan with and without 
contrast performed prior to biopsy. 
• Laboratory tests (conducted under standard of care) 
• Scheduling for Surgical Removal of the Tumor and biopsy for Pathological 
Diagnosis or Tumor Biopsy for Pathological Diagnosis, MGMT gene methylation 
status, IDH-1 mutation status, and for ChemoID (at the same time). 
• Medical Record Review 
 
5.3.2 Visit 2 post-op visit 
• Physical Exam (conducted under standard of care) 
• Vital Signs (conducted under standard of care) 
• Brain Imaging by MRI or CT scan preferentially with contrast 
• Review of Pathology report 
• Review of MGMT methylation gene promoter status 
• Review of IDH-1 mutation status 
• Registration to the trial of recurrent GBM patients  
• Randomization of patients to receive either standard of care chemotherapy chosen by 
the physician (ARM 1) or ChemoID guided therapy (ARM 2). 
 
5.3.3 Visit 3 post-radiation visit 
• Physical Exam (conducted under standard of care) 
• Vital Signs (conducted under standard of care) 
• Under standard of care, Brain Imaging by MRI or CT scan preferentially with 
contrast 
 


 
 
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5.3.4 Visit 4 start of treatment visits 
• Physical Exam (conducted under standard of care) 
• Vital Signs (conducted under standard of care) 
• Laboratory tests (conducted under standard of care) 
• For participants randomly assigned to ChemoID guided therapy, review of ChemoID 
test results 
• Start study intervention by dispensing study drug according to study arms’ 
assignment and their cohorts 
• Assess possible adverse events  
• Medical Record Review 
• Better Health-Related Quality of Life (HRQOL) assessment based on questionnaires, 
addressing physical, psychological, emotional, and social issues to be completed 
before treatment start. 
 
5.4 Follow-up Phase 
See Table 1 for the procedures and assessments to be performed during this phase of the 
study.  Participants will be followed for three years according to standard-of-care intervals 
by neurologic and neurosurgical clinical assessments as detailed in Table 1: schedule of 
study procedures. 
Participant will be assessed at follow-up visits following standard-of-care radiation and 
surgery treatments and chemotherapy drugs will be dispensed according to groups and 
cohorts. Drug compliance and adverse event assessment will also be performed. 
Outpatient visits will be completed as close to the scheduled visit dates as possible. The visit 
window is ± 7-14 days from the intended date of the visit.  If needed, outpatient visit 
procedures may require more than one day to complete, if so, the date of the history and 
physical exam will be considered the visit date.  
Follow-up visits consist of a clinical evaluation with particular attention to neurological 
function, seizures and corticosteroid use as per standard-of-care management of the disease. 
HRQoL.  Laboratory tests of blood counts, glucose level, and blood count, liver function 
tests are indicated if the participant is receiving chemotherapy, corticosteroids and anti-
epileptic drugs.   
Labwork and brain imaging collected at visits as per standard-of-care. 
At 6 and 12 months after Visit 24 there will be a phone call to assess survival status.  


 
 
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20 
Following are the steps involved with this phase of the study: 
 
5.4.1 Visit 1 
• Physical Exam 
• Vital Signs 
• Laboratory tests if performed as per standard of care 
• Brain Imaging by MRI or CT scan preferentially with contrast if performed as per 
standard of care 
• Continue study intervention according to study arms’ assignment and their cohorts 
• Medical Record Review 
• Better Health-Related Quality of Life (HRQOL) assessment based on questionnaires, 
addressing physical, psychological, emotional, and social issues. 
 
5.4.2 Visit 2 
• Physical Exam 
• Vital Signs 
• Brain Imaging by MRI or CT scan preferentially with contrast if performed as per 
standard of care 
• Continue study intervention according to study arms’ assignment and their cohorts 
• Medical Record Review 
• Better Health-Related Quality of Life (HRQOL) assessment based on questionnaires, 
addressing physical, psychological, emotional, and social issues. 
 
5.4.3 Visit 3 
• Physical Exam 
• Vital Signs 
• Laboratory tests if performed as per standard of care 


 
 
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• Brain Imaging by MRI or CT scan preferentially with contrast if performed as per 
standard of care 
• Continue study intervention according to study arms’ assignment and their cohorts 
• Medical Record Review 
• Better Health-Related Quality of Life (HRQOL) assessment based on questionnaires, 
addressing physical, psychological, emotional, and social issues. 
 
 
5.4.4 Visit 4 
• Physical Exam 
• Vital Signs 
• Brain Imaging by MRI or CT scan preferentially with contrast if performed as per 
standard of care 
• Continue study intervention according to study arms’ assignment and their cohorts 
• Medical Record Review 
• Better Health-Related Quality of Life (HRQOL) assessment based on questionnaires, 
addressing physical, psychological, emotional, and social issues. 
 
5.4.5 Visit 5 
• Physical Exam 
• Vital Signs 
• Laboratory tests if performed as per standard of care 
• Brain Imaging by MRI or CT scan preferentially with contrast if performed as per 
standard of care 
• Continue study intervention according to study arms’ assignment and their cohorts 
• Medical Record Review 
• Better Health-Related Quality of Life (HRQOL) assessment based on questionnaires, 
addressing physical, psychological, emotional, and social issues. 


 
 
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5.4.6 Visit 6 
• Physical Exam 
• Vital Signs 
• Brain Imaging by MRI or CT scan preferentially with contrast if performed as per 
standard of care 
• Continue study intervention according to study arms’ assignment and their cohorts 
• Medical Record Review 
• Better Health-Related Quality of Life (HRQOL) assessment based on questionnaires, 
addressing physical, psychological, emotional, and social issues. 
 
5.4.7 Visit 7 
• Physical Exam 
• Vital Signs 
• Laboratory tests if performed as per standard of care 
• Brain Imaging by MRI or CT scan preferentially with contrast if performed as per 
standard of care 
• Continue study intervention according to study arms’ assignment and their cohorts 
• Medical Record Review 
• Better Health-Related Quality of Life (HRQOL) assessment based on questionnaires, 
addressing physical, psychological, emotional, and social issues. 
 
5.4.8 Visit 8 
• Physical Exam 
• Vital Signs 
• Brain Imaging by MRI or CT scan preferentially with contrast if performed as per 
standard of care 
• Continue study intervention according to study arms’ assignment and their cohorts 


 
 
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• Medical Record Review 
• Better Health-Related Quality of Life (HRQOL) assessment based on questionnaires, 
addressing physical, psychological, emotional, and social issues. 
 
5.4.9 Visit 9 
• Physical Exam 
• Vital Signs 
• Laboratory tests if performed as per standard of care 
• Brain Imaging by MRI or CT scan preferentially with contrast if performed as per 
standard of care 
• Continue study intervention according to study arms’ assignment and their cohorts 
• Medical Record Review 
• Better Health-Related Quality of Life (HRQOL) assessment based on questionnaires, 
addressing physical, psychological, emotional, and social issues. 
 
5.4.10 Visit 10 
• Physical Exam 
• Vital Signs 
• Brain Imaging by MRI or CT scan preferentially with contrast if performed as per 
standard of care 
• Continue study intervention according to study arms’ assignment and their cohorts 
• Medical Record Review 
• Better Health-Related Quality of Life (HRQOL) assessment based on questionnaires, 
addressing physical, psychological, emotional, and social issues. 
 
5.4.11 Visit 11 
• Physical Exam 
• Vital Signs 


 
 
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24 
• Laboratory tests if performed as per standard of care 
• Brain Imaging by MRI or CT scan preferentially with contrast if performed as per 
standard of care 
• Continue study intervention according to study arms’ assignment and their cohorts 
• Medical Record Review 
• Better Health-Related Quality of Life (HRQOL) assessment based on questionnaires, 
addressing physical, psychological, emotional, and social issues. 
 
5.4.12 Visit 12: 
• Physical Exam 
• Vital Signs 
• Brain Imaging by MRI or CT scan preferentially with contrast if performed as per 
standard of care 
• Continue study intervention according to study arms’ assignment and their cohorts 
• Medical Record Review 
• Better Health-Related Quality of Life (HRQOL) assessment based on questionnaires, 
addressing physical, psychological, emotional, and social issues. 
 
5.4.13 Visits 13 to 23 
Repeat as visits 1-11 schedules 
 
5.4.14 Visit 24 
• Physical Exam 
• Vital Signs 
• Laboratory tests if performed as per standard of care 
• Brain Imaging by MRI or CT scan preferentially with contrast if performed as per 
standard of care if indicated 
• Continue study intervention according to study arms’ assignment and their cohorts 


 
 
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25 
• Medical Record Review 
• Better Health-Related Quality of Life (HRQOL) assessment based on questionnaires, 
addressing physical, psychological, emotional, and social issues. 
 
5.4.15 Follow-up phone calls 
• At 6 and 12 months following Visit 24 there will be a phone call to assess survival 
status.  
 
5.5 Unscheduled Visits 
Unscheduled visits will be handled as part of standard-of-care visits. Participant will be 
assessed by: 
• Physical Exam 
• Vital Signs 
• Laboratory tests if performed as per standard of care 
• Brain Imaging by MRI or CT scan preferentially with contrast if performed as per 
standard of care 
• Medical Record Review 
• Better Health-Related Quality of Life (HRQOL) assessment based on questionnaires, 
addressing physical, psychological, emotional, and social issues. 
 
5.6 Concomitant Medication 
Record all concomitant (OTC & prescription) taken 30 days prior to the screening visit 
through study termination.  
 
5.7 Rescue Medication Administration 
N/A 
5.8 Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care.  They 
may also be discontinued from the study at the discretion of the Investigator for lack of 
adherence to study treatment or visit schedules, and AEs.  The Investigator or the Sponsor 


 
 
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may also withdraw subjects who violate the study plan, or to protect the subject for reasons 
of safety or for administrative reasons.  It will be documented whether or not each subject 
completes the clinical study. If the Investigator becomes aware of any serious, related 
adverse events after the subject completes or withdraws from the study, they will be 
recorded in the source documents and on the CRF. 
5.8.1 Early Termination Study Visit 
Subjects who withdraw from the study will be requested to have all procedures enumerated 
for Visit 24 as the early termination visit.  
 
6 
STUDY EVALUATIONS AND MEASUREMENTS 
All laboratory exams and imaging monitoring procedure, measurements and therapeutic 
interventions listed in Section 4 will be done following standard-of-care procedure. 
Better Health-Related Quality of Life (HRQOL) will be assessed using standardized self-
reported, and validated questionnaires, addressing physical, psychological, emotional, and 
social issues. 
 
6.1 Screening and Monitoring Evaluations and Measurements 
6.1.1 Medical Record Review 
Include a listing of the variables that will be abstracted from the medical chart (paper or 
electronic). 
• Age 
• Gender 
• Weight 
• Pathology report 
• Steroid and other medication doses over the course of treatment 
• ChemoID test results 
• MGMT gene methylation status 
• IDH-1 mutation status 
• Chemotherapy regimens including doses 
• Radiation therapy schedule and doses 


 
 
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• All brain imaging including but not limited to DICOM images of MRI and or CT 
scans as well as reports 
• Clinical assessment of disease at baseline and during the course of therapy from 
neuro-oncologic progress notes 
• Health-Related Quality of Life (HRQOL) questionnaires addressing physical, 
psychological, emotional, and social issues. 
 
6.1.2 Physical Examination 
Medical history, height and weight, physical examination by neurological exam, 
demographic characteristics (age, gender, race) will be performed and collected. 
6.1.3 Vital Signs 
Blood pressure will be measured with an automated device or with an aneroid 
sphygmomanometer on the right arm with patient sitting.  
6.1.4 Laboratory Evaluations 
Blood sampling will be performed for the following laboratory evaluations: 
6.1.4.1 Hematology 
Hematology testing will be performed at the laboratory at the investigators institution 
(Blood collection of both CMP and CBC with Differential within 7-days prior to starting 
Temodar.  Blood collection weekly during treatment, and then weekly for 3 more weeks 
after chemotherapy stops.  Then SOC is every 2 weeks for labs). 
Table: Clinical Laboratory Tests 
Category 
Tests 
Hematology 
RBC, hemoglobin, hematocrit, platelet count, WBC with 
differential 
blood glucose levels 
Liver function tests 
Complete metabolic panel 
Renal function tests 
Complete metabolic panel 
6.1.4.2 Pregnancy Testing 
A urine or a serum pregnancy test will be performed for female subjects ≥ 18 years of age 
who are physically capable of becoming pregnant. 
6.1.5 Other Evaluations, Measures 
Other evaluations will concern review of brain Imaging by MRI or CT scan preferentially 
with contrast, pathology report, MGMT methylation gene promoter status, IDH-1 mutation 


 
 
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status, ChemoID assay test results, Better Health-Related Quality of Life (HRQOL) 
assessment based on questionnaires, addressing physical, psychological, emotional, and 
social issues. 
 
6.2 Efficacy Evaluations 
Under standard-of-care, clinical response to therapy will be evaluated according to the 2D 
Response Assessment in Neuro-Oncology (RANO) criteria, in which in addition to contrast 
enhancement, tumor extension on T2- and fluid-attenuated inversion recovery (FLAIR)-
weighted MRI are evaluated (8). Furthermore, an assessment of neurological function and 
corticosteroid use will be included. 
 
6.3 Safety Evaluation 
Subject safety will be monitored by adverse events, vital signs, physical examinations, and 
clinical laboratory data.    
 
 
 
 
 
 
 
 
 
 
 
7 
STATISTICAL CONSIDERATIONS 
7.1 Primary Endpoint 
The primary endpoint of this study is: 
• Median Overall Survival (OS) 
 
7.2 Secondary Endpoints 
Secondary endpoints will include the following: 
• Overall Survival at 6, 9, and 12 months (OS6mo, OS9mo, OS12mo) 
• Median Progression Free Survival (PFS)  
• Progression Free Survival at 4, 6, 9, and 12 months (PFS4mo, PFS6mo, PFS9mo, 
PFS12mo) 
• Objective tumor response measured by RANO (Response Assessment in Neuro-
Oncology Criteria) 
• Time to recurrence  
• Health-Related Quality of Life (HRQOL)  
However, the ChemoID assay is considered a non-significant risk (NSR) assay for the 
patients because the drugs prescribed to the participants are part of the standard-of-care 
practice for the treated disease. Any side effects from administering chemotherapies are not 
associated with the assay per se. Any morbidity associated with tissue sampling is also part 
of standard-of-care and its expected risks are not associated with the assay.


 
 
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7.3 Statistical Methods 
7.3.1 Baseline Data  
Initial analyses will involve data cleaning, variable development, and exploratory data 
analyses. We will use standard summaries to describe baseline characteristic distributions in 
terms of centrality, spread, shape, and possible outliers by arm, cohort and treatment group. 
Graphical explorations will emphasize examination of the nature and extent of potential 
nonlinear relationships on the appropriate modeling scale (e.g. natural, log, logit, etc.) 
7.3.2 Efficacy Analysis 
The primary analysis will be based on an intention to treat approach and will include all 
subjects randomized at baseline. The primary efficacy outcome is overall survival (OS) in 
months.  This outcome will be compared between patients randomized to ChemoID guided 
chemotherapy (ChemoID) versus standard of care (SOC).  OS comparisons will be 
examined using Cox Proportional Hazard Models for Overall Survival with baseline hazards 
stratified by site and medians will be compared between treatment arms. Models examining 
adjustments for sex, race, age, and tumor stage will be constructed, as well as for moderating 
effects of these variables (subpopulation investigations).  
Secondary analyses will include logistic regression models for Overall and Progression Free 
Survival at 4, 6, 9, and 12 months, Cox Proportional Hazard Models for Progression Free 
Survival in months, Generalized Linear Models (GLMs) for analyses on objective tumor 
response (RANO), and Health-Related Quality of Life (HRQOL). Generalized Linear Mixed 
Models (GLMMs) will be used for analyses of changes in any additional repeated outcome 
measures to incorporate within-person associations and examine distributions of participant-
specific declines. Huber-White robust standard errors will be used, and multiple variance 
structures will be investigated to examine sensitivity of primary analyses to the choice of 
association model. Shared Parameter Models (SPM) will be used to examine any potential 
informative missing data effects. 
7.3.3 Safety Analysis 
All evaluable subjects entered into the study at Baseline will be included in the safety 
analysis. AE/SAE frequencies and probabilities and confidence intervals will be compared 
between the treatment groups. 
 
7.4 Sample Size and Power 
For our primary analyses comparing median Overall Survival (OS), with N=150, a 1:1 ratio 
between treatment groups, an overall alpha rate of 5% and interim analysis described below, 
we will have over 80% power to detect a relative decrease in in the hazard of mortality of 
HR < 0.55 or more at the final analysis.  
 


 
 
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7.5 Interim Analysis 
Interim analyses are based upon the alpha spending approach of Lan and DeMets. 
According to the established final sample size and assumed 105 primary events needed for 
the final analysis. We will conduct two planned interim analyses. One will be triggered 
when 35 patients have died. The trial may be stopped for efficacy at this point if both the 
observed HR is less than or equal to 0.55 and its associated p-value < 0.0167. Assuming the 
trial moves forward, the second interim analysis will occur once 70 participants have died. 
The trial may be stopped for efficacy at this point if both the observed HR is less than or 
equal to 0.55 and its associated p-value < 0.0218. The final analysis will occur at 105 deaths, 
and the nominal p-value to declare efficacy will be 0.0278.  
  
 
 


 
 
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8 
STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) 
8.1 Description 
This clinical study utilizes FDA approved chemotherapies that are currently used for the 
treatment of recurrent Glioblastoma and recurrent WHO III Glioma. Following is a table 
illustrating the list of chemotherapy agents used in this study. 
List of Current Chemotherapeutic Agents and suggested Combinations on the ChemoID® 
GBM Drug Panel 
  
Single Drug 
Dose 
1 
Carboplatin 
350 mg/m2 or 4 AUC 
2 
Irinotecan 
125 mg/m2 
3 
Etoposide 
50 mg/m2 
4 
BCNU 
100 mg/m2 
5 
CCNU 
100 mg/m2 
6 
Temozolomide 
150-200 mg/m2 
7 
Procarbazine 
60 mg/m2 
8 
Vincristine 
1.4 mg/m2 
9 
Imatinib 
400 mg 
  
Drug Combination 
Dose 
1 
Procarbazine 
60 mg/m2 
  
CCNU 
100 mg/m2 
  
Vincristine 
1.4 mg/m2 
2 
Carboplatin 
350 mg/m2 or 4 AUC 
  
Irinotecan 
125 mg/m2 
3 
Carboplatin 
350 mg/m2 or 4 AUC 
  
Etoposide 
50 mg/m2 
4 
Temozolomide 
50 mg/m2 
  
Etoposide 
50 mg/m2 
5 
Temozolomide 
50 mg/m2 
  
Imatinib 
200 mg 
 
 


 
 
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9 
SAFETY MANAGEMENT 
The ChemoID assay is a low risk assay for the patients. Any side effects from administering 
chemotherapies are not associated with the assay per se.  Any morbidity associated with the 
sampling is part of standard-of-care and its expected risks are not associated with the assay. 
We will record and report only adverse events of grade 3 and 4.  
 
9.1 Clinical Adverse Events 
Clinical adverse events due to standard-of-care drugs (AEs) will be monitored throughout 
the study. This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs 
reporting of adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0.  
9.1.1 
 
Definition of an Adverse Event (AE)  
Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  Therefore, an AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product (attribution of unrelated, unlikely, possible, probable, 
or definite (International Conference on Harmonisation [ICH], E2A, E6).   
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug.  
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited manner.  
 
Following is a definition of the meaning of each Adverse Events term. 
 
Grades:  Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 
with unique clinical descriptions of severity for each AE based on this general guideline: 
 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*. 
Grade 3 Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
Grade 5 Death related to AE. 
 


 
 
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9.1.1.1 Percentage of frequency of potential adverse events and serious events related to 
chemotherapy drugs used in this study 
Carboplatin 
Irinotecan 
Etoposide 
BCNU 
CCNU 
Leukopenia (26-
97%) 
Anemia (>90%) 
Leukopenia (60-91%) 
Convulsions (19%) 
Nausea (54%) 
Neutropenia 
(21-96%) 
Leukopenia 
(>90%) 
Nausea and Vomiting 
(30-40%) 
Hemiplegia (19%) 
Vomiting (54%) 
Nausea (81-
93%) 
Neutropenia 
(>90%) 
Thrombocytopenia 
(28-41%) 
Headache (15%) 
Neurotoxicity 
Vomiting (81-
93%) 
Thrombocytope
nia (>90%) 
Alopecia (20-90%) 
Metabolic disorder (14%) 
Myelosuppression 
(delayed 4-5 weeks) 
Anemia (14-
90%) 
Elevated 
bilirubin (88%) 
Anorexia (13%) 
Somnolence (14%) 
Ataxia 
Magnesium loss 
(43-61%) 
Diarrhea (85%) 
Diarrhea (13%) 
Fever (12%) 
Lethargy 
Thrombocytope
nia (33-66%) 
Nausea (79%) 
Leukopenia (60-91%) 
Confusion (10%) 
Disorientation 
Alopecia (2-
49%) 
Asthenia (70%) 
Anemia (≤33%) 
Aphasia (9%) 
Stomatitis 
Asthenia (11-
41%) 
Abdominal pain 
(63%) 
Pancytopenia (7%) 
Nausea (8%) 
Mucositis 
Elevated 
alkaline 
phosphatase (29-
37%) 
Vomiting (60%) 
Stomatitis (6%) 
Vomiting (8%) 
Pulmonary fibrosis 
(rare) 
Central 
neurotoxicity (5-
26%) 
Alopecia (43%) 
Hepatic toxicity (3%) 
Pain (7%) 
Pulmonary toxicity 
Elevated AST 
(19-20%) 
Fever (42%) 
Type 1 
hypersensitivity (2%) 
Rash (5%) 
Elevated LFTs 
Peripheral 
neuropathy (6-
15%) 
Constipation 
(41%) 
Orthostatic 
hypotension (1-2%) 
Abscess (4%) 
Leukemia 
Immune 
hypersensitivity 
reaction (2-
9.2%) 
Anorexia (34%) 
Peripheral neuropathy 
(1-2%) 
Cranial edema (4%) 
Renal toxicity 
Elevated 
bilirubin (5%) 
Mucositis (32%) 
  
ICP elevation (4%) 
Hepatic toxicity 
  
Pain (31%) 
  
Meningitis (4%) 
Infertility 
  
Dyspnea (28%) 
  
Hyperglycemia (3%) 
Alopecia 
  
Cough (27%) 
  
HTN (3%) 
Optic atrophy (rare) 
  
Dizziness (23%) 
  
Constipation (2%)  
  
  
Infection (22%) 
  
Diarrhea (2%) 
  
  
Rash (19%) 
  
Dizziness (2%)  
  
  
Abdominal 
fullness (10%) 
  
Depression (2%) 
  
  
AST increased 
(10%) 
  
Greater myelotoxicity 
reported when co-
administered with 
cimetidine 
  


 
 
WIRB 20172720 
 
 
 
34 
  
Dyspepsia 
(10%), 
  
Cardiac disorders: 
Tachycardia and chest 
pain 
  
  
Edema (10%) 
  
Eye disorders: 
conjunctival edema, 
conjunctival hemorrhage, 
blurred vision and loss of 
depth perception 
  
  
Ascites/jaundice 
(9%) 
  
Gastrointestinal toxicity: 
Nausea, vomiting, 
anorexia, and diarrhea 
  
  
Vasodilation 
(9%) 
  
Hepatotoxicity: Increased 
transaminase, increased 
alkaline phosphatase, 
increased bilirubin levels 
Infections and 
Infestations:  
  
  
Thromboemboli
sm (9%) 
  
Infections: Opportunistic 
infections (including with 
fatal outcome) 
  
  
Hypotension 
(6%) 
  
Neoplasms benign, 
malignant and unspecified 
(including cysts and 
polyps): Acute leukemia, 
bone marrow dysplasia 
  
  
Neutropenic 
fever (2-6%) 
  
Nephrotoxicity: 
Progressive azotemia, 
decrease in kidney size, 
renal failure 
  
  
  
  
Nervous system disorders: 
Headaches, 
encephalopathy, and 
seizures 
  
  
  
  
Pulmonary toxicity: 
Pneumonitis, interstitial 
lung disease 
  
  
  
  
Reproductive system and 
breast disorders: 
gynecomastia 
  
  
  
  
Skin and subcutaneous 
tissue disorders: Burning 
sensation, 
hyperpigmentation,   
swelling, pain, erythema, 
skin necrosis, alopecia, 
allergic reaction  
  
  
  
  
Vascular Disorders: 
Veno-occlusive disease 
  
 
 
 


 
 
WIRB 20172720 
 
 
 
35 
Temozolomide 
Procarbazine 
Vincristine 
Imatinib 
Alopecia (55-69%) 
Neuropathy 
Alopecia (20-70%) 
Edema (53%) 
Lymphopenia (55%) 
Neurotoxicity 
Peripheral neuropathy 
Neutropenia (Grade 3: 7-27%; 
Grade 4: 3-48%) 
Nausea (53%) 
Nausea 
Paresthesia 
Nausea (43%) 
Vomiting (42%) 
Vomiting 
Sensory loss 
Muscle cramps (35%) 
Headache (41%) 
Pleural effusion 
Acute uric acid 
nephropathy 
Musculoskeletal pain (34%) 
Fatigue (34%) 
Myelosuppression 
Loss of deep-tendon 
reflexes 
Thrombocytopenia (Grade 3: 1-
31%; Grade 4: 1-34%) 
Constipation (33%) 
Heinz bodies 
Hypertension 
Rash (32%) 
Anorexia (9-27%) 
Hepatic dysfunction  
Hypotension 
Fatigue (31%) 
Convulsions (23%) 
Impairment of 
fertility 
Nausea 
Diarrhea (30%) 
Thrombocytopenia 
(19%) 
  
Vomiting 
Headache (29%) 
Rash (8-19%) 
  
Constipation 
Arthralgia (27%) 
Hemiparesis (18%) 
  
Paralytic ileus 
Abd pain (23%) 
Diarrhea (16%) 
  
Myelosuppression 
Myalgia (21%) 
Neutropenia (14%) 
  
Leukopenia 
Nasopharyngitis (19%)  
Fever (13%) 
  
Gait changes 
Hemorrhage (19%) 
Asthenia (13%) 
  
Jaw pain  
Vomiting (15%) 
Dizziness (12%) 
  
Aspermia 
Dyspepsia (15%) 
Peripheral edema (11%) 
  
Amenorrhea 
Cough (13%) 
Viral infections (11%) 
  
  
Dizziness (13%) 
Amnesia (10%) 
  
  
URT infection (13%) 
Insomnia (10%) 
  
  
Fever (12%) 
Abdominal pain (5-9%) 
  
  
Weight gain (12%) 
Ataxia (8%) 
  
  
Hepatotoxicity (6-12%) 
Back pain (8%) 
  
  
Insomnia (11%) 
Paresis (8%) 
  
  
Hematologic toxicity (1-64%) 
URI (8%) 
  
  
Flushing  
Urinary incontinence 
(8%) 
  
  
Palpitation 
UTI (8%) 
  
  
Dry skin 
Abnormal vision (5-8%) 
  
  
Erythema 
Pruritus (5-8%) 
  
  
Metabolic hyperglycemia 
Breast pain (6%) 
  
  
Stomatitis/mucositis 
Depression (6%) 
  
  
Lymphopenia 
Confusion (5%) 
  
  
Congestive heart failure and left 
ventricular dysfunction 
Myalgia (5%) 
  
  
Hypereosinophilic cardiac toxicity 
Weight gain (5%) 
  
  
Aplastic anemia 
Anemia (4%) 
  
  
Atrial fibrillation 
Erythema (1%) 
  
  
Avascular necrosis 


 
 
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36 
  
  
  
Cardiac failure 
  
  
  
Cardiogenic shock 
  
  
  
Embolism 
  
  
  
Eosinophilia 
  
  
  
Hypothyroidism 
  
  
  
Growth retardation in children and 
adolescents 
  
  
  
Tumor lysis syndrome 
  
  
  
Impairments related to driving and 
using machinery 
 
 
 


 
 
WIRB 20172720 
 
 
 
37 
 
9.2 Adverse Event Reporting 
Since the study procedures are not greater than minimal risk, SAEs are not expected. If any 
unanticipated problems related to the research involving risks to subjects or others happen 
during the course of this study (including SAEs) they will be reported to the IRB in 
accordance with ASRI-WPAHS IRB SOP 011: Unanticipated Problems Involving Risks to 
Subjects. AEs that are not serious but that are notable and could involve risks to subjects 
will be summarized in narrative or other format and submitted to the IRB at the time of 
continuing review.  
 
10 STUDY ADMINISTRATION 
10.1 Treatment Assignment Methods 
Participants will be randomly assigned to the study arms according to their main 
characteristics:  
Consented participants affected by resectable recurrent GBM or grade III glioma able to 
provide a fresh tumor biopsy. 
 
10.1.1 Randomization 
Participants will be randomized using a statistical random number generator using REDCap.  
Study investigators will be kept blind to the schedule.  A password-protected web-portal 
(REDCap) will be available for study-personnel to access patient randomization assignments 
 
10.1.2 Blinding 
Investigators and trial personnel will not be aware of ChemoID test results for patients in 
ARM 1 (standard of care chosen by physician) until the end of the study.  The ChemoID lab 
will not release test results for these subjects.   
Investigators and trial personnel will request to the ChemoID lab the test results only for 
subject assigned to the ChemoID-guided therapy (ARM 2). 
Subjects will be blinded to the arm they have been randomized to. 
10.1.3 Unblinding 
Not allowed 
 


 
 
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38 
10.2 Data Collection and Management 
Primary records (source documents) and case report forms (CRF) will be collected in paper 
format and subsequently entered to either Medidata Rave or REDCap, two secure cloud–
based clinical data management systems used to electronically capture, manage, and report 
clinical research data.  Both systems provide web-based case report forms, real-time data 
entry validation, audit trails, and the ability to set up a calendar to schedule and track critical 
clinical study events such as radiological imaging, participant visits, etc. In addition, the 
software allows identifying and protecting fields that contain Protected Health Information 
(PHI) data by employing user rights that are set by the study administrator to control who 
can view, modify, or add data and/or forms. All activities are system logged, and are 
available in a full audit trail. Confidentiality will be maintained by keeping a master list 
containing patient health information (PHI) by using a subject identification (ID) number 
that have only a study ID number.  Both systems also offer a data export utility, which 
enables to export data in an automated manner into formats that are compatible with 
commonly used statistical analysis packages such as SAS, SPSS, Stata, and R. 
 
10.3 Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy and that the Investigator and other site 
personnel will not use such data and records for any purpose other than conducting the 
study. ChemoID personnel are HIPAA trained and certified.  No identifiable data will be 
used for future study without first obtaining IRB approval. The investigator will obtain a 
data use agreement between the provider (the PI) of the data and any recipient researchers 
before sharing a limited dataset (PHI limited to dates and zip codes).  
 
10.4 Regulatory and Ethical Considerations 
This study will be conducted in accordance with Good Clinical Practice (GCP) requirements 
described in the current revision of International Conference on Harmonisation of Technical 
Requirements of Pharmaceuticals for Human Use (ICH) Guidelines and all applicable 
regulations, including current United States Code of Federal Regulations (CFR), Title 21, 
Parts 11, 50, 54, 56, and 312 and Title 45, Part 164.  Compliance with these regulations and 
guidelines also constitutes compliance with the ethical principles described in the current 
revision of the Declaration of Helsinki.  This study will also be carried out in accordance 
with local legal requirements. 
Prior to initiating this study, this protocol will be reviewed and approved by the appropriate 
local IRB.  The composition and conduct of this committee will conform to the United 
States CFR.   
The IRB will also review and approve the site’s informed consent form (ICF), other written 
information provided to the patient that may be used for patient recruitment.   


 
 
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39 
If it is necessary to amend the protocol or the ICF during the study, the Investigator will be 
responsible for ensuring that the IRB reviews and approves these amended documents. An 
IRB approval of the amended protocol and/or ICF must be obtained in writing before 
implementation of the amended procedures and before new patients are consented to 
participate in the study using the amended version of the ICF. 
 
10.4.1 Data and Safety Monitoring Plan 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
   
Only grades 3 or 4 SAE are reportable to the Sponsor. The Sponsor will notify the DSMB 
Chair each time a grade 3 or 4 SAE occurs.  The DSMB will evaluate unblinded SAE data 
when 25 GBM patients have completed 1 month of follow-up (Visit 1). Other safety data, 
such as laboratory data will also be evaluated by the DSMB as appropriate.  Monitoring of 
key safety endpoints will be conducted as described above, and if rates significantly exceed 
pre-set thresholds, ChemoID sponsor will be notified and information will be supplied to the 
DSMB. All SAEs, at least possibly related, will also be sent to the DSMB chair.  The Project 
Officer (or designee) will be responsible for reviewing the SAE materials to determine if the 
documents are complete.  If there are any concerns regarding the type or frequency of the 
event, the Project Officer will request that the DSMB Executive Secretary notify the DSMB 
Chair.  The DSMB Chair will review the SAE materials, determine if the information is 
complete, determine if additional DSMB review is required and make recommendations to 
sponsor concerning continuation of the study.  The data-coordinating center (DCC) will 
prepare semi-annual summary reports of all AEs/SAEs for the Project Officer and Chair.  
Semi-annual reports will be made available on a secure website and the Project Officer and 
DSMB Chair will be notified by e-mail when the materials are posted.  
 
10.4.2 Risk Assessment 
Risks for this study are not greater than minimal because the chemotherapy drugs used for 
treatments of participants in all the study arms are all FDA approved agents to treat recurrent 
glioblastoma and recurrent WHO III Glioma. Physicians treating participants enrolled in 
study arms and/or cohorts in which the treatment is guided by the ChemoID assay will 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Interim analyses will be conducted at times coincident with regularly scheduled meetings of 
the appointed Data and Safety Monitoring Board (DSMB) at approximately six-month 
intervals.
The ChemoID assay is a non-significant risk assay for the patients. Any side effects from 
administering chemotherapies are not associated with the assay per se. Any morbidity 
associated with the sampling is part of standard-of-care and its expected risks are not 
associated with the assay. This is a prospective randomized clinical study in which the risk 
of the participants is low
also because all the drugs used are already FDA approved to treat the specific disease. This 
clinical study is not evaluating the efficacy of the drugs, but the ability of the ChemoID test 
to predict drugs that will provide better outcomes to the patients who are treated with
ChemoID guided therapy vs. subjects treated with empirically chose drugs.


 
 
WIRB 20172720 
 
 
 
40 
choose treatments from those indicated as high-cell kill from the test, but always taking into 
consideration the performance status and general clinical condition of the patients. 
The adaptive design of the study will minimize the risks of harm to participants by providing 
the principal investigator the ability to suspend the study after 18 months, if higher than 
standard-of-care risk to therapeutic intervention will be identified. 
 
10.4.3 Potential Benefits of Trial Participation 
The information obtained from the test will be used to understand if the chemo sensitivity 
assay using CSCs in conjunction with the bulk tumor cells can help to achieve better 
outcomes in cancer patients. 
Collectively, results of clinical response to empirical therapy or to chemotherapy agents 
suggested by chemosensitivity testing will be used to determine the predictive value of 
chemosensitivity testing to clinical response.   
The potential direct benefits include better response to chemotherapy and clinical outcome 
as well as the possible avoidance of potentially ineffective, costly and morbidity producing 
chemotherapies. Indirect benefits include reducing the chance of ineffective chemotherapy, 
unnecessary hospitalizations, and lowering the health-care cost. 
 
10.4.4 Risk-Benefit Assessment 
Although there are several chemotherapy agents used to treat recurring GBMs and WHO III 
Gliomas, there is no standard of care treatment approved for these patients. Selection of 
effective chemotherapy is extremely important when therapy is first initiated. In fact, 
administration of ineffective anticancer therapy is associated with unnecessary toxicity and 
the development of more aggressive cancer cell clones that are resistant to subsequent 
therapies. The ability to initially choose the most effective chemotherapy may help to avoid 
the physical, emotional, and financial burden to patients of ineffective therapy, thereby 
improving their quality of life. Each time patients are treated, they have a chance of relapse, 
and their cancer will likely become more resistant to therapy. Presently used anticancer 
drugs have a high rate of failure, and cell culture chemotherapy testing has been used to 
identify which drugs are more likely to be effective against a particular tumor type. 
Measuring the response of the tumor cells to drug exposure is valuable in any situation in 
which there is a choice between two or more treatments ChemoID is the first and only drug 
response assay available in the clinics that examine CSCs that contribute to treatment 
resistance, and tumor recurrence from solid tumors.  
Results from previous ChemoID clinical studies indicate that a drug response assay that 
targets specifically targets CSCs along with bulk tumor cells may be a very useful tool for 
optimizing treatment selection when first-line therapy fails and when there are multiple 
clinically acceptable and equivalent treatments available. Furthermore, the ChemoID study 
results indicate that individualized functional drug response assays provide more treatment 
options with improved outcomes for many recurrent patients than are currently achieved by 


 
 
WIRB 20172720 
 
 
 
41 
empiric population-based treatment. This data suggests that it is reasonable to prospectively 
utilize a functional test like ChemoID drug response assay to assist clinicians in the optimal 
prioritization of therapy for recurring GBM and WHO III Glioma patients. 
 
10.5 Recruitment Strategy 
Patients coming to clinical visit and/or neuro-oncologic consult for symptoms and/or 
imaging findings related to the presence of a recurring glioblastoma will be approached as 
eligible subjects for the study.  Following a discussion on their medical treatment options, 
candidates will sign an informed consent to be enrolled in the study.  Subjects will be 
included in the study if the pathology report of their tumor biopsy will confirm the presence 
of recurrent glioblastoma multiforme. 
 
10.6 Informed Consent/Assent and HIPAA Authorization 
Before being admitted to the clinical study, all patients will consent in writing to participate.  
Informed consent may be obtained from a legal authorized representative when the person is 
not competent, incapacitated, or otherwise unable to make an informed judgment. An 
informed consent form (ICF) will be given to each patient, which will contain all United 
States federally required elements, all ICH-required elements, and Health Insurance 
Portability and Accountability Act (HIPAA) authorization information in language that is 
understandable to the patient.  
The process of obtaining the informed consent will be in compliance with all federal 
regulations, ICH requirements, and local laws.   
The Investigator will review the study with each patient.  The review will include the nature, 
scope, procedures, and possible consequences of the patient's participation in the study.  The 
ICF and review will be in a form understandable to the patient.  The Investigator or designee 
and the patient must both sign and date the ICF after review and before the patient can 
participate in the study.  The patient will receive a copy of the signed and dated form, and 
the original will be retained in the site study files.  The Investigator or his/her designee will 
emphasize to the patient that study participation is entirely voluntary and that consent 
regarding study participation may be withdrawn at any time without penalty or loss of 
benefits to which the patient is otherwise entitled. 
If the ICF is amended during the study, the Investigator must follow all applicable 
regulatory requirements pertaining to approval of the amended ICF by the IRB/IEC.  The 
site must use the amended consent form for all new patients and repeat the consent process 
with the amended ICF for any ongoing patients. 
Patients’ names will remain confidential and will not be included in the database.  Only 
patient number, patient initials, and birth date will be recorded in the data system.  If the 
patient name appears on any other document collected (e.g., hospital discharge summary), 
the name will be obliterated before the document is transmitted.  All study findings will be 


 
 
WIRB 20172720 
 
 
 
42 
stored in paper format databases.  The patients will give explicit permission for 
representatives of the Sponsor, regulatory authorities, and the IRB to inspect their medical 
records to verify the information collected.   
Patients will be informed that all personal information made available for inspection will be 
handled in the strictest confidence and in accordance with all state, local, and federal data 
protection/privacy laws, including, without limitation, the HIPAA. 
All participants in the will provide written authorization to disclose private health 
information either as a part of the written ICF or as a separate authorization form.  The 
authorization will contain all required elements specified by 45 CFR 164, and will contain a 
waiver of patient access to study-related private health information until the conclusion of 
the clinical study.  The authorization will remain valid and in full force and effect until the 
first to occur of (1) the expiration of 2 years after the study therapy is approved for the 
indication being studied, or (2) the expiration of 2 years after the research program is 
discontinued.  Individual patient medical information obtained during this study is 
confidential and its disclosure to third parties (other than those mentioned in this Section 
9.7) is strictly prohibited.  In addition, medical information obtained during this study may 
be provided to the patient's personal physician or to other appropriate medical personnel 
when required in connection with the patient's continued health and welfare. 
The Investigator will maintain a personal patient identification list (patient and treatment 
numbers with the corresponding patient names) to enable records to be identified. 
Confidentiality will be maintained by keeping a master list containing patient health 
information (PHI) and subject identification (ID) number separate from paper data forms 
that have only a study ID number. The master list will be on a separate computer, removable 
disk drive or in a locked file cabinet and therefore, this form of data is considered “coded”. 
 
11 PUBLICATION OF CLINICAL DATA 
Patient data collected will be examined and analyzed independently by a group of 
radiologists and biostatisticians.   
Complete trial data and end of study statistics will be provided to the principal investigators 
of the multicenter clinical study and the publication write up will be done in collaboration 
between the investigators. 
 
 


 
 
WIRB 20172720 
 
 
 
43 
 
12 REFERENCES 
1. 
Claudio PP, Mathis SE, Nande R, Alberico A, Neto W, Lawrence L, et al. Novel 
chemosensitivity assay for targeting cancer stem-like cells in brain tumors. . J Clin Oncol. 
2014;32:suppl; abstr e13012. 
2. 
Claudio PP, Mathis SE, Nande R, Lawrence L, Alberico A, Julien TJ, et al. 
ChemoID Assay for Glioblastoma. J Clin Oncol. 2015;33:suppl; abstr e13028. 
3. 
Claudio PP, Valluri J, editors. Chemosensitivity assay for targeting cancer stem-like 
cells in malignant brain tumors. Cancer Stem Cell Conference 2014 August 2014; 
Cleveland, OH. 
4. 
Claudio PP, Valluri J, editors. Prospective Analysis of Chemo-Predictive Assay for 
Targeting Cancer Stem Cells in Glioblastoma Patients. Cancer Stem Cell Conference 2016; 
Cleveland, OH. 
5. 
Claudio PP, Valluri J, Mathis SE, Alberico A, Alberico T, Denvir J, et al. 
Chemopredictive assay for patients with primary brain tumors. J Clin Oncol. 2013;31:suppl: 
abstract 2089. 
6. 
Howard CM, Alberico A, Valluri J, Griswold M, Claudio PP. Analysis of chemo-
predictive assay for targeting cancer stem cells in 41 glioblastoma patients. J Clin Oncol. 
2017:suppl; abstr e13544. 
7. 
Howard CM, Valluri J, Alberico A, Julien T, Mazagri R, Marsh R, et al. Analysis of 
Chemopredictive Assay for Targeting Cancer Stem Cells in Glioblastoma Patients. Transl 
Oncol. 2017;10(2):241-54. 
8. 
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et 
al. Updated response assessment criteria for high-grade gliomas: response assessment in 
neuro-oncology working group. J Clin Oncol. 2010;28(11):1963-72. 
9. 
Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. 
Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin 
Oncol. 2009;27(28):4733-40. 
10. 
Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, 
et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 
2014;370(8):699-708. 
11. 
Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. 
Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J 
Med. 2014;370(8):709-22. 
 
 
 
 


 
 
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44 
 
APPENDIX 
 
1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent (IC)


 
APPROVED 
 
Jan 04, 2018 
 
WIRB 
 
 
 
Page 1 of 10 
 
 
INFORMED CONSENT FORM AND AUTHORIZATION TO DISCLOSE PROTECTED 
HEALTH INFORMATION FOR A RESEARCH STUDY 
 
TITLE: 
Standard Chemotherapy versus Chemotherapy Chosen by Cancer 
Stem Cell Chemosensitivity Testing in the Management of Patients 
with Recurrent Glioblastoma Multiforme (GBM). 
 
PROTOCOL NO.: 
CG01-GBM 
 
WIRB® Protocol #20172720 
 
SPONSOR: 
ChemoID 
 
INVESTIGATOR: 
Tulika Ranjan, MD 
 
Allegheny Cancer Center 
 
5th Floor 
 
Allegheny General Hospital 
 
320 E. North Avenue 
 
Pittsburgh, PA 15212 
 
United States 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Tulika Ranjan, MD 
 
412-770-3039 (24 Hours) 
 
1 - 
Introduction:  You are invited to be in a research study.  Research studies are designed 
to gain scientific knowledge that may help other people in the future.  There may be risks 
associated with being part of research studies.  If there are any risks involved in this study 
then they will be described in this consent.  Your participation is voluntary.  Please take your 
time to make your decision, and ask your research doctor or research staff to explain any 
words or information that you do not understand. 
 
2 - 
What you should know about a research study: 
 
• Someone will explain this research study to you. 
• You volunteer to be in a research study. 
• Whether or not you take part is up to you. 
• You can choose not to take part in the research study. 
• You can agree to take part now and later change your mind. 
• Whatever you decide it will not be held against you. 
• Feel free to ask all the questions you want before you decide. 
 


 
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3 - 
Who can I talk to if I have questions? 
 
If you have questions, concerns, or complaints, or think the research has hurt you, you should 
contact the principal investigator – Tulika Ranjan, MD, 412-770-3039, she can be reached  
24 hours/day. 
 
If you have questions about your rights as a research subject or if you have questions, concerns 
or complaints about the research or for any of the reasons listed below: 
 
• Your questions, concerns, or complaints are not being answered by the research team. 
• You cannot reach the research team. 
• You want to talk to someone besides the research team. 
• You have questions about your rights as a research subject. 
• You want to get information or provide input about this research 
 
You may contact: 
 
Western Institutional Review Board® (WIRB®) 
1019 39th Avenue SE Suite 120 
Puyallup, Washington  98374-2115 
Telephone:  1-800-562-4789 or 360-252-2500 
E-mail:  Help@wirb.com 
 
WIRB is a group of people who perform independent review of research. 
 
WIRB will not be able to answer some study-specific questions, such as questions about 
appointment times.  However, you may contact WIRB if the research staff cannot be reached or 
if you wish to talk to someone other than the research staff. 
 
If you have any questions regarding Allegheny Health Network Research, please contact  
1-844-577-4621. 
 
4 - 
Why is this study being done? 
 
The investigational purpose of this study is to screen chemotherapy drugs currently used for the 
care of recurrent glioblastoma (a form of brain cancer) and to determine the most effective 
treatment based on results from a chemosensitivity assay. 
 
Chemosensitivity drug assay refers to testing a patient's own cancer cells in the laboratory to 
drugs that are to be used to treat the patient's cancer. 
 
Following surgery, you will be treated either as per chemotherapy agents chosen by the 
physician or with chemotherapies as suggested by the results of the chemosensitivity testing. 
 
We would like to determine if patients treated with drugs predicted by the chemosensitivity test 
have better outcomes than patients treated with drugs chosen by the treating physician. 


 
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5 - 
How long will the research last? 
 
We expect that you will be in this research study for 3 years.  This study is designed to follow 
you for long-term survival as such – your doctor and his/her staff would like to follow your long-
term health status for a period of not more than 36 months, by accessing your hospital records. 
 
You can decide to stop participating at any time.  If you decide to stop participating in the study 
we encourage you to talk to the investigators or study staff to discuss what follow up care and 
testing could be most helpful for you.  The study doctor may stop you from taking part in this 
study at any time if he/she believes it is in your best interest; if you do not follow the study rules; 
or if the study is stopped. If you decide to withdraw or if you are removed from the study, all 
data generated up to the date of withdrawal from the study will be collected. 
 
6 - 
How many people will be studied? 
 
About three hundred (300) people will take part in this study over a three year period. Allegheny 
Health Network is projected to enroll 60 participants per year in the trial; two additional sites are 
projected to enroll 40 participants per year. 
 
7 - 
What happens if I say yes, I want to be in this research? 
 
This study uses sample specimens obtained by the same surgical procedures that patients have to 
routinely undergo for the treatment of recurrent brain cancer. 
 
Surgical resections are part of the established standard-of-care procedures to treat recurrent brain 
cancer. You will be asked to sign a separate consent form for this procedure as per standard of 
care. 
 
As per standard-of-care, tumor biopsies from the surgical resections will be sent to the pathology 
laboratory for pathological confirmation of recurrent GBM and for MGMT methylation status 
assessment. 
 
Biopsies will be also sent to the ChemoID laboratory for drug response assay assessment, which 
is a laboratory-developed test (LDT). 
 
Participants will be randomized to receive either ChemoID guided chemotherapy with standard-
of-care drugs, or standard-of-care drugs chosen by the Physician. 
 
A computer will choose the treatment-group that you are assigned.  Neither you nor the study 
doctor will choose what treatment-group you will be assigned. You will have one in two chance 
of being assigned to each treatment-group. You will not be told in which treatment-group you 
are, however your study doctor will know. 
 


 
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All diagnostic procedures (except for ChemoID test), therapeutic management and follow-up 
procedures will be conducted under standard-of-care for the disease. 
 
• Administration of chemotherapy drugs will be under standard-of-care management of 
the disease. 
• Follow-up visits will consist of a clinical evaluation with particular attention to 
neurological function, seizures and corticosteroid use, as per standard-of-care 
management of the disease. 
• Indicated laboratory tests of blood counts, glucose level, and blood count, liver function 
tests, and the administration of corticosteroids and anti-epileptic drugs will be as per 
standard-of-care management of the disease. 
• Radiological imaging with CT and/or MRI preferentially with contrast will be 
performed every 2 months as per standard-of-care management and follow-up of the 
disease. 
 
8 - 
What happens if I say no, I do not want to be in this research? 
 
You may decide not to take part in the research and it will not be held against you. Refusal to 
participate will involve no penalty or loss of benefits to which you are otherwise entitled. 
 
9 - 
What happens if I say yes, but I change my mind later? 
 
If you agree to take part in the research now and stop at any time it will not be held against you. 
You may discontinue participation at any time without penalty or loss of benefits to which you 
are otherwise entitled. 
 
10 - What are the risks of the study? 
 
Being in this study involves some risk to you, which are the same as the risks listed on your 
surgical consent. You should discuss with the study staff the risks of being in this study, which 
are the same as the risks of being treated with standard-of-care chemotherapy and radiation. 
 
You should talk to your study doctor about any side effects that you have while taking part in the 
study. You will be provided with a US Package insert listing the risks and side effects for each 
drug that you will receive. Again, feel free to discuss with the study doctor this information and 
ask any questions about anything you feel needs to be explained to you. 
 
There may be side effects that we cannot predict.  You should tell the research staff about all the 
medications, vitamins and supplements you take and any medical conditions you have.  This may 
help avoid side effects, interactions and other risks. 
 


 
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PREGNANCY 
Pregnant women or nursing mothers cannot participate in the study. Women of childbearing age 
must have a negative pregnancy test within 72 hours prior to study entry. Women of childbearing 
potential must practice medically approved contraceptive precautions.  The study doctor will 
explain the pregnancy risks and the length and precautions you will need to take (depending of 
the treatment drugs you will be assigned to) not to become pregnant. 
 
11 - Will being in this study help me anyway? 
 
We cannot promise any benefits to you or others from your taking part in this research. However, 
possible benefits include prolonged response to treatment.  Also, we hope the information 
learned from this study will benefit other people in the future. 
 
12 - What other choices are there? 
 
You do not have to be in this study to receive treatment. You may still receive the same 
chemotherapy treatments without being in the study. 
 
The study doctor will discuss your alternative treatments option with you including comfort care. 
 
If you decide that you don’t want any more active treatment, one of your options is called “comfort care.”  
Comfort care includes pain medication and other support.  It aims to maintain your comfort and dignity 
rather than cure disease.  Usually this care can be provided at home.  
 
If you think you might prefer comfort care, please discuss this with your family, friends and your doctor. 
 
13 - Will my information be kept confidential? 
 
Your identity and medical records and data related to this study will be kept confidential, except 
as required by law and except for inspections by the Department of Health and Human Services, 
the Food and Drug Administration the sponsor (ChemoID), Allegheny Health Network, the 
Allegheny Health Network Research Institute, the Institutional Review Board (the committee 
that reviews, approves and oversees research) and the AHN Compliance Office.  By law, anyone 
who looks at your records must keep them completely confidential. This is done to make sure 
that we are doing the study in the right way.  They also need to make sure that we are protecting 
your rights and your safety. 
 
Results of the research may be published for scientific purposes or presented to scientific groups; 
however, your identity will not be revealed. 
 
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. 
 
Federal law provides additional protections of your personal health information. These are 
described below in the HIPAA Authorization Section below. 
 


 
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14 - Can I be removed from the research without my OK? 
 
The investigator in charge of the research study or the sponsor can remove you from the research 
study without your approval.  Possible reasons for removal include failure to follow instructions 
of the research staff or if the investigator in charge decides that the research study is no longer in 
your best interest. The sponsor can also end the research study early. 
 
We will tell you about any new information that may affect your health, welfare, or choice to 
stay in the research. 
 
15 - Are there costs of taking part in this study? 
 
There are no costs to you for taking part in this study.  The chemosensitivity assay that is 
required for this study will be provided to you at no cost and will be paid for by the study 
sponsor, ChemoID. 
 
Costs for your regular medical care, which is not related to this study, will be your own 
responsibility. This kind of research study is not expected to result in any additional costs to you 
or your insurance company.  If you require medical care for your glioblastoma or other health 
problems, as part of your routine care (care you receive even if you do not participate in this 
research study), either you or your insurance carrier will be billed for these charges.  The cost for 
the standard-of-care items will be billed to you or your insurance company as usual.  If you 
require additional medical care for your glioblastoma or other health problems, as part of your 
standard medical care, either you or your insurance carrier will be billed for these additional 
charges.  Please talk with the study doctor about any expected costs or health insurance 
problems. 
 
16 - Will I be paid to participate in this study? 
 
You will not be paid for your participation in this research study. 
 
17 - What if I am injured while taking part in this study? 
 
If you are injured or made sick while taking part in this research study, emergency medical 
treatment will be provided at the usual charge.  No funds have been set aside by Allegheny 
Health Network or Allegheny Health Network Research Institute to pay you in case you are 
injured. You do not waive any of your legal rights to compensation, if any, by signing this form. 
 
18 - What are my rights as a research study participant? 
 
Taking part in this study is voluntary.  You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled.  If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. 
 


 
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19 - Authorization to Use and Disclose Individually Identifiable Health 
Information for a Research Study 
 
Before you can take part in this research study, the Allegheny Health Network is required to 
obtain your authorization to use and/or disclose (release) your health information.  This section 
describes to you how, and to whom, your health information will be used and/or disclosed 
(shared) while you are participating in this research study.  It is important that you read this 
carefully. Allegheny Health Network and its’ researchers are required by law to protect your 
health information. 
 
The following is a list of health information that will be used and/or disclosed: 
 
• Age 
• Gender 
• Weight 
• Pathology report 
• Record of steroid and other medication doses over the course of treatment 
• ChemoID test results 
• MGMT gene methylation status 
• IDH-1 mutation status 
• Chemotherapy regimens including doses 
• Radiation therapy schedule and doses (if part of therapy regimen) 
• All brain imaging including but not limited to DICOM images of MRI and or CT scans as 
well as reports 
• Clinical assessment of disease at baseline and during the course of therapy from neuro-
oncologic progress notes 
• Health-Related Quality of Life (HRQOL) questionnaires addressing physical, 
psychological, emotional, and social issues. 
 
The following is a list of entities that may use and/or disclose your health information as 
part of this study: 
 
Internal Oversight 
Those who oversee the study will have access to your health information, including the 
following: 
• Allegheny Health Network (AHN) 
• Allegheny Health Network Research Institute 
• AHN Compliance Office 
• Study Doctor and Study Staff 
 
Governmental Oversight 
Your health information may also be shared with government agencies that have oversight of the 
study or to whom access is required under the law: 
• Department of Health and Human Services (DHHS) 
• Food and Drug Administration (FDA) 
 


 
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Others Outside Allegheny Health Network  
The following persons and/or organizations outside of Allegheny Health Network may also use, 
disclose and receive your health information in connection with this study: 
• Sponsor (and companies owned/affiliated with sponsor): ChemoID may need to view 
your medical records to make sure the study is being completed correctly. 
• Western Institutional Review Board® (WIRB®) is a group of people who review the 
ethics of human research. 
• A Data Safety Monitoring Board (DSMB) will be responsible to monitor data quality 
management and ongoing assessment of safety. 
• ChemoID laboratory at the Translational Genomics Research Institute (TGRI) in Cabell 
Huntington Hospital will test patient's own cancer cells to drugs that are to be used to 
treat the patient's cancer. 
 
In order to participate in this study, you must agree to share your health information with the 
persons and organizations listed above. If these persons or organizations that you authorize to 
receive and/or use protected health information, are not health plans, covered health care 
providers or health care clearinghouses subject to federal health information privacy laws, they 
may further disclose the protected health information and it may no longer be protected by the 
federal health information privacy laws. 
 
Expiration of Authorization 
This authorization will not expire unless you revoke it in writing. You may revoke or end this 
authorization by writing to the Principal Investigator: 
 
Tulika Ranjan, MD 
Allegheny Health Network 
320 East North Avenue 
Pittsburgh, PA 15212 
 
If you revoke your authorization, you will also be removed from the study.  Revoking your 
authorization only affects the use and sharing of your health information after the written request 
is received.  Any health information obtained prior to receiving the written request may be used 
to maintain the integrity of the study. 
 


 
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Authorization 
By signing this document (authorization), you authorize that your health information can be used 
and/or disclosed as described. 
 
Your access to your protected health information created or obtained by Allegheny Health 
Network in the course of the research (that includes treatment) may be temporarily suspended for 
as long as the research is in progress.  By signing this document, you are agreeing to the denial 
of access to your protected health information, created for the research, while you are 
participating in this research study. Your access to your protected health information will be 
reinstated upon completion of the research. 
 
If you choose to not sign this document, you will not be permitted to participate in this research 
study. 
 
20 - Consent for Future Use of Specimens 
 
We would like to keep your specimens that are left over from the study for future research.  
Reports about future research will not be given to you or your regular doctor. These reports will 
not be put in your health record. 
 
The specimens will be coded in such a manner that it should not be possible for others to find out 
that they came from you. 
 
Even if you decide now that your specimens can be used for future research, you can later 
request, for up to 2 years from the end of your participation in the study, that they not be used for 
this research. To make this request, contact the study site and let them know that you now do not 
want your specimens to be used for research.  Please understand that if the code identifying your 
specimens has been removed, we will not be able to find out which specimens are yours.  In this 
case, they may still be used for research.  Results from research that was done using your 
specimens before you changed your mind can still be used by the researchers.  There is no end 
date for how long your specimens will be kept. 
 
You agree that your leftover specimens may be used for other research purposes. 
 
Please Initial. 
 
 
Yes, You agree 
 
No, you do not agree 
 


 
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21 - Consent  
 
Your signature below indicates your permission to take part in this research and to the use and 
disclosure of your protected health information: 
 
 
 
 
Signature of Subject 
 
Date 
 
 
Time 
 
Printed Name of Subject 
 
 
 
Investigator Signature  
 
Date 
 
 
Time 
 
Printed Name of Investigator 
 
 
 
 
Signature of Witness to Signature 
 
 
 
Printed Name of Person Witnessing Signature 
 
Date 
 
 
Time 
 
My signature indicates that the information in the consent document and any other written 
information was accurately explained to, and apparently understood by, the subject, and that 
consent was freely given by the subject. 
 
 Check box ONLY if the witness is an “impartial” witness - an individual (greater than 18 years of 
age) with no affiliations to the patient (e.g. not a relative) and/or to the research study (e.g. not a 
study coordinator).  An “impartial” witness is only required when a “short form” consent form is 
used or the subject is unable to read the consent form and the written informed consent document is 
read and comprehended by the subject or the subject’s legally authorized representative and oral 
consent is given by either the subject or the subject’s legally authorized representative. 
 
 
 
Signature of Witness to Signature 
 
Date 
 
Time 
 
Printed Name of Witness to Signature