Clinical trial NCT03393000
Conditions: Glioblastoma
Sponsor: Diffusion Pharmaceuticals Inc
Start date: 2018-01-16; Completion date: 2020-11-06
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Open-label, randomized, controlled, phase 3 safety and efficacy registration trial.

Subjects will be randomized at baseline to the standard of care for first-line treatment of glioblastoma plus Trans Sodium Crocetinate (TSC) or the standard of care.

The standard of care for GBM will consist of temozolomide plus radiation therapy for 6 weeks followed by 28 days of rest followed by 6 cycles of post-radiation temozolomide treatment.

Detailed description:
During the radiation treatment period subjects will receive:

1. Focal radiation delivered as 60 Gray/30 fractions scheduled at 2 Gray/day for 5 days each week (Monday through Friday) for 6 weeks.
2. Temozolomide 75mg/m2 orally once daily (usually administered the night preceding each radiation session) starting the evening before the first radiation session over a period of 42 calendar days with a maximum of 49 days.
3. TSC 0.25 mg/kg IV for 3 days each week (Monday, Wednesday, Friday) administered between 45 to 60 minutes prior to each radiation session.

Pneumocystis carinii pneumonia (PCP) prophylaxis is required during Temozolomide + radiation administration, regardless of lymphocyte count and is to continue until recovery of lymphocyte count to less than or equal to Grade 1.

During the 28-day rest period all subjects will receive no treatment.

During the post-radiation 6-cycle temozolomide treatment period subjects will receive:

All subjects will receive: 28-day oral temozolomide (150 mg/m2 first cycle and 200 mg/m2 all subsequent cycles as tolerated) administered on Day 1-5 (Monday through Friday) of each 28-day cycle.

Controls: Will receive oral temozolomide at night at home per the standard of care.

Subjects randomized to TSC: Will receive TSC 1.5 mg/kg (or the dose recommended by the Data Safety Monitoring Board) 1.5 to 2 hours before their temozolomide dose during the daytime for 3 days during the first week of each 28-day cycle (Days 1, 3, 5: Monday, Wednesday, Friday). The Tuesday, Thursday doses will be given at night at home. Long-acting antiemetics may be administered prior to daytime temozolomide dosing on Days 1, 3, 5.

In accordance with the FDA directive of August 22, 2017 the safety, tolerability and pharmacokinetics of TSC at doses between 0.25 mg/kg and up to 1.5 mg/kg in combination with concomitant temozolomide will be assessed via a dose escalation run-in prior to initiating the randomized trial.

The first eight (8) subjects enrolled in the 100-206 trial will be assigned (not randomized between treatments) at Baseline to undergo radiation plus temozolomide plus TSC treatment (0.25 mg/kg) for 6 weekly cycles followed by 4 weeks of rest in standard fashion. At the Week 10 clinic visit the same eight (8) subjects will be assigned to treatment with 2 subjects each assigned to TSC at doses of 0.25, 0.50, 1.0 and 1.5 mg/kg.

The first eight (8) subjects will be studied in parallel and all for two full 28-day cycles with inclusion of appropriate blood sampling collection for TSC and temozolomide pharmacokinetics.

The Data Safety Monitoring Board will examine the resultant safety data after 2 full cycles (Weeks 11 through 18 of post-radiation temozolomide treatment period; Days 1 to 56).

The eight (8) subjects that are a part of the dose-escalation run-in will continue at their assigned TSC dose (0.25, 0.5, 1.0, 1.5 mg/kg) for the Week 19 TSC dosing period.

The Data Safety Monitoring Board will recommend an acceptable TSC dose, if different than 1.5 mg/kg, for the post-radiation temozolomide treatment period prior to the Week 23 TSC dosing period for the eight (8) subjects that are a part of the dose-escalation run-in.

Thereafter, subjects will enter the 100-206 trial and be randomized at Baseline between TSC plus standard of care or the standard of care.

Arms: arm 1: Trans Sodium Crocetinate plus the Standard of Care (SOC): SOC composed of radiation and temozolomide for 6 weeks followed by 4 weeks of rest followed by six (6) 28-day cycles of temozolomide arm 2: Standard of Care (SOC): SOC composed of radiation and temozolomide for 6 weeks followed by 4 weeks of rest followed by six (6) 28-day cycles of temozolomide
Interventions: intervention 1: Trans Sodium Crocetinate plus SOC intervention 2: Standard of Care (SOC)
Intervention descriptions: intervention 1: Trans Sodium Crocetinate (TSC) plus the Standard of Care (SOC): SOC composed of radiation and temozolomide for 6 weeks followed by 4 weeks of rest followed by six (6) 28-day cycles of temozolomide intervention 2: Standard of Care (SOC): SOC composed of radiation and temozolomide for 6 weeks followed by 4 weeks of rest followed by six (6) 28-day cycles of temozolomide

Protocol documents:
Prot_SAP_000.pdf: 
Diffusion Pharmaceuticals Inc 
Confidential 
TSC injectable 
Protocol 100-206: May 11, 2018  
 
Page 1 of 43 
DOCUMENT TYPE: 
Clinical protocol 
DOCUMENT NUMBER: 
 
NCT: 
100-206 
 
NCT03393000 
COMPOUND: 
Trans Sodium Crocetinate 
STUDY TITLE: 
Open-label, Randomized, Controlled, Phase 3 Safety and 
Efficacy Study of Trans Sodium Crocetinate (TSC) with 
Radiation Therapy and Temozolomide in Newly 
Diagnosed Glioblastoma (GBM) Biopsy-Only Subjects 
CLINICAL PHASE: 
3 
INDICATION: 
Radiation and Chemotherapy Sensitizer for Use with 
Radiation and Temozolomide in the Treatment of 
Glioblastoma 
IND NUMBER: 
78,410 
SPONSOR: 
Diffusion Pharmaceuticals Inc. 
1317 Carlton Avenue, Suite 200 
Charlottesville, VA 22902 
DOCUMENT 
VERSION/STATUS: 
 
Version 1.4 Final 
DOCUMENT 
RELEASE/AMENDMENT 
DATE: 
Amendment 4:  May 11, 2018 
Amendment 3:  January 12, 2018 
Amendment 2:  October 13, 2017 
Amendment 1:  August 29, 2017 
July 10, 2017 
 
 
 
 
 
 
 
 
Property of Diffusion Pharmaceuticals Inc. 
Confidential – this document or its contents may not be used, divulged, published, or disclosed without consent of 
Diffusion Pharmaceuticals Inc. 


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Protocol 100-206: May 11, 2018  
 
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SYNOPSIS 
Title 
Open-label, Randomized, Controlled, Phase 3 Safety and Efficacy 
Study of Trans Sodium Crocetinate (TSC) with Radiation Therapy 
and Temozolomide in Newly Diagnosed Glioblastoma (GBM) 
Biopsy-Only Subjects 
Protocol No. 
100-206 
Study Phase 
3 
Study Design 
Open-label, randomized, controlled, phase 3 safety and efficacy 
registration trial. 
Subjects will be randomized at Baseline to the standard of care for 
first-line treatment of GBM plus Trans Sodium Crocetinate (TSC) or  
the standard of care. 
The standard of care for GBM will consist of temozolomide plus 
radiation therapy (RT) for 6 weeks followed by 28 days of rest 
followed by 6 cycles of post-radiation temozolomide treatment. 
TSC will be administered during both the RT and post-radiation 
temozolomide treatment periods to those subjects so randomized. 
During the RT treatment period subjects will receive: 
1. Focal RT delivered as 60Gy/30 fractions scheduled at 2Gy/day for 
5 days each week (Monday through Friday) for 6 weeks. 
2. Temozolomide 75 mg/m2 orally once daily (usually administered 
the night preceeding each RT session) starting the evening before 
the first RT session over a period of 42 calendar days with a 
maximum of 49 days. 
3. TSC 0.25mg/kg IV for 3 days each week (e.g. Monday, 
Wednesday, Friday or other schedule that supplies at minimum 3 
TSC doses per week) administered between 45 to 60 minutes prior 
to each RT session.  
Pneumocystis carinii pneumonia (PCP) prophylaxis is required during 
Temozolomide + RT administration, regardless of lymphocyte count, 
and is to continue until recovery of lymphocyte count to less than or 
equal to Grade 1.  
During the 28-day rest period all subjects will receive no treatment. 


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During the post-radiation 6-cycle temozolomide treatment period 
subjects will receive: 
All subjects will receive:  28-day oral temozolomide (150 mg/m2 first 
cycle and 200 mg/m2 all subsequent cycles as tolerated) administered 
on Day 1-5 (Monday through Friday) of each 28-day cycle. 
Controls:  Will receive oral temozolomide at night at home per the 
standard of care. 
Subjects randomized to TSC:  Will receive TSC 1.5 mg/kg (or the 
dose recommended by the DSMB) 1.5 to 2 hours before their 
temozolomide dose during the daytime for 3 days during the first 
week of each 28-day cycle (Days 1, 3, 5: e.g. Monday, Wednesday, 
Friday  or other schedule that supplies at minimum 3 TSC doses per 
week).  Long-acting antiemetics may be administered prior to daytime 
temozolomide dosing on Days 1, 3, 5. 
In accordance with the FDA directive of August 22, 2017 the safety, 
tolerability and PK of TSC at doses between 0.25 mg/kg and up to 
1.5 mg/kg in combination with conconmitant temozolomide will be 
assessed via a dose escalation run-in prior to initiaing the 
randomized trial.  
The first eight (8) subjects enrolled in the 100-206 trial will be 
assigned (not randomized between treatments) at Baseline to undergo 
RT plus temozolomide plus TSC treatment (0.25 mg/kg) for 6 weekly 
cycles followed by 4 weeks of rest in standard fashion. At the Week 
10 clinic visit the same eight (8) subjects will be assigned to treatment 
with 2 subjects each assigned to TSC at doses of 0.25, 0.50, 1.0 and 
1.5 mg/kg.  More than eight (8) subjects may need to be enrolled to 
achieve eight (8) who complete two full cycles of temozolomide 
adjuvant treatment. 
The first eight (8) subjects will be studied in parallel and all for two 
full 28-day cycles with inclusion of appropriate blood sampling 
collection for TSC and temozolomide PK. 
The Data Safety Monitoring Board (DSMB) will examine the 
resultant safety data after 2 full cycles (Weeks 11 through 18 of 
post-radiation temozolomide treatment period; Days 1 to 56).   
 


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The eight (8) subjects that are a part of the dose-escalation run-in 
will continue at their assigned TSC dose (0.25, 0.5, 1.0, 1.5 mg/kg) 
for the Week 19 TSC dosing period. 
The DSMB will recommend an acceptable TSC dose, if different 
than 1.5 mg/kg, for the post-radiation temozolomide treatment 
period prior to the Week 23 TSC dosing period for the eight (8) 
subjects that are a part of the dose-escalation run-in.  
Thereafter, subjects will enter the 100-206 trial and be randomized 
at Baseline between TSC plus standard of care or the standard of 
care. 
Study 
Population 
To be eligible for the study, subjects must be 18 to 70 years of age, 
male or female and have histologically confirmed GBM.  Biopsy-only 
subjects with measurable contrast enhancing disease with limited 
disturbance of tumor during biopsy are included.  Gross total 
resection, partial resection and debulking GBM subjects are excluded.  
Local surgical and pathology reports will constitute adequate 
documentation for study inclusion. 
Adequate hematologic, renal and liver function testing must be 
completed within 5 weeks of randomization under this protocol.  
Subjects must not have had prior RT, chemotherapy, immunotherapy, 
biologic therapy, or hormonal therapy for their brain tumor.  Subjects 
must have a KPS ≥ 60, and subject or subject healthcare power of 
attorney must provide written informed consent.   
Number of 
Subjects 
Up to 300 will be screened; 264 randomized to complete 236 subjects. 
Study Centers 
Up to 100 sites 
Objective 
To assess the safety and efficacy of TSC as first-line treatment for 
biopsy-only GBM when administered with the standard of care 
consisting of RT/temozolomide for 6 weeks, followed by 28 day rest 
followed by post-radiation temozolomide-only treatment for six 28-
day cycles. 


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Study 
Overview 
Subjects will be randomized to TSC plus standard of care or standard 
of care only as the contemporaneous control, at Baseline.  The study 
is not blinded because a sham treatment in this study is considered 
both ethically unsound, extraordinarily challenging given the highly 
colorized test article, and that all key outcome measures are objective. 
 
The start of RT treatment is recommended to begin >3 but ≤ 5 weeks 
after biopsy.   
 
All subjects will be given RT for 30 fractions, as tolerated.  TSC 
treatment may continue as long as the subject is receiving RT, 
regardless of whether temozolomide has been discontinued or not 
administered.   
 
Baseline procedures will include medical history, physical exam, 
clinical chemistries, including CBC with differential and platelet 
count, urinalysis, and 12-lead ECG.   
 
An MRI scan must be performed ≤ 7 days before the start of RT.  An 
MRI performed according to the International Standardized Brain 
Tumor Imaging Protocol (BTIP) 4 weeks after completion of 
concurrent radiation and temozolomide treatment (Week 10) will 
serve as the Baseline scan for assessment of response and progression 
for use in mRANO assessments. MRI scans will be then be performed 
at 8 week intervals (Weeks 18, 26, 34) through Week 34 and 
thereafter at approximately 8 week intervals per standard of care 
through Week 106.  Assessment of the MRI results will be done by 
independent central imaging review in a blinded manner.  If no tumor 
is present, tumor size will be recorded as zero. 
 
The concomitant use of corticosteroids (permissive stable dose or 
decreasing dose), anticonvulsants and other chemotherapy agents as 
part of the subject’s treatment plan for GBM will be documented.  
 
The EQ-5D-5L instrument will be used to assess health related quality 
of life.  
 
PK/PD 
Substudy 
In accordance with the FDA directive (end-of-phase 2 meeting, 
August 2015), a pharmacokinetic (PK) and pharmacodynamic (PD) 
substudy will be performed in a subpopulation of all subjects 
receiving TSC. 
 


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Protocol 100-206: May 11, 2018 
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The pharmacokinetics of TSC will be evaluated using Population PK 
methodologies. 
The Population PK analysis will include an assessment of covariates, 
(e.g., subject demographics).  An evaluation of exposure-response 
(PK/PD) will be performed for relevant safety and efficacy endpoints. 
Safety 
Assessments 
Adverse events will be graded and promptly recorded according to the 
revised National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4 during the study and 
up to 30 days following the completion of TSC study drug dosing.   
Safety assessments will include physical exam, concomitant 
medication usage, vital signs, 12-lead ECG, and clinical chemistries, 
including CBC and urinalysis.   
Progression of disease and disease-related death will not be 
considered adverse events.   
Adverse events that occur > 30-days after the last dose of TSC will 
not be collected as part of the study database.   
Documentation of concomitant medications > 30-days after the last 
dose of TSC will be limited to corticosteroid, bevacizumab, 
chemotherapy, and anticonvulsant use. 
Statistical 
Analysis Plan 
Primary Efficacy Endpoint: 
•
Overall survival (OS)
Secondary Efficacy Endpoints: 
•
Progression Free Survival (PFS); per RANO 2010 and
modified RANO (mRANO 2017)
•
Objective Response Rate (ORR); per RANO 2010 and
modified RANO (mRANO) 2017
•
Karnofsky Performance Scale (KPS)
•
Quality of Life –EQ-5D-5L - subject reported outcome
•
Corticosteroid use
•
Anticonvulsant medication use
•
Chemotherapy for recurrent glioma
•
Changes in peripheral neuropathy, leukopenia,
thrombocytopenia - graded according to CTCAE


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Protocol 100-206: May 11, 2018 
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Exploratory Endpoints 
•
Evaluate tumor growth kinetics of measurable target lesions
•
Time to unequivocal progression of enhancing non-target
lesions
Safety: 
•
Adverse events
•
Physical exam
•
Concomitant medication usage
•
Vital signs
•
12-lead ECG
•
Clinical laboratory
Safety assessments will be made at Baseline (Day 1), during the RT 
treatment period, prior to the post-radiation temozolomide treatment 
period (Week 10), and during the post-radiation temozolomide 
treatment period (Weeks 11 through 34). 
The Sponsor will collect all radiological images for all randomized 
subjects, for independent central imaging review in a blinded manner. 
Secondary radiographic endpoint assessments includes the assessment 
of PFS and ORR using both RANO and mRANO as secondary 
endpoints.  The pre-treatment MRI scan will be used as the baseline 
comparison scan per RANO criteria while the Week 10 post-treatment 
MRI will be used as baseline for all subsequent follow-ups using 
mRANO.  
An independent Data Safety Monitoring Board (DSMB) will be 
established to review the safety profile during the dose-escalation run-
in and recommend the dose of TSC for the post-radiation 
temozolomide treatment period (if different than 1.5 mg/kg), review 
the safety profile relative to the established stopping rule and 
generally safeguard the interests of study participants.  The details 
regarding the functioning of the DSMB will be outlined in the DSMB 
charter. 
RANO/mRANO results were not included in results section. Please see rationale 
immediately below:
 
The 100-206 trial included a 19-patient lead-in dose escalation study to assess safety and tolerability. This 
was to be followed by a randomized study during which RANO/mRANO assessments would be performed.  
The Sponsor did not have adequate resources to fully support the randomized portion of the 100-206 study 
and commencement of enrollment in the randomized portion of the trial was suspended. 


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Protocol 100-206: May 11, 2018 
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•
Vital signs
•
12-lead ECG
•
Clinical laboratory
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design 
This is an open-label, randomized, controlled, safety and efficacy phase 3 registration study in 
adults with newly diagnosed GBM (biopsy-only). 
To be eligible for the study, subjects must be 18 to 70 years of age, male or female, and have 
histologically confirmed GBM.  Biopsy-only with measurable contrast enhancing disease with 
limited disturbance of tumor during biopsy are included.  Gross total resection, partial resection 
and debulking GBM subjects are excluded.  Local surgical and pathology reports will constitute 
adequate documentation of histology for study inclusion. 
Adequate hematologic, renal and liver function testing must be completed within 5 weeks of 
randomization.  Subjects must not have had prior RT, chemotherapy, immunotherapy, biologic 
therapy, or hormonal therapy for their brain tumor(s).  Subjects must have a KPS ≥ 60.  Subject 
or subject caregiver with healthcare power of attorney must provide written informed consent.  
Treatment under this protocol should begin >3 but ≤ 5 weeks after surgery.  
All procedures to qualify the subject should be completed within 5 weeks of randomization. 
Those assessments include physical exam, clinical chemistries, including a CBC with differential 
and platelet count, medical resonance imaging (MRI) scans, urinalysis, 12-lead ECG and 
medical history.  Subjects will be assigned to treatment arms sequentially in chronological order. 
Radiation plus Temozolomide Treatment (RT) 
RT treatment is recommended to begin >3 but < 5 weeks after biopsy.  All subjects will receive 
standard-of-care RT and temozolomide ± TSC for 6 weeks. Subjects will receive TSC 
0.25mg/kg IV plus the standard of care or only the standard of care for 3 days each week (e.g. 
Monday, Wednesday, Friday, or other schedule that supplies at minimum 3 TSC doses per week) 
and all receive SOC for the other 2 days (Tuesday, Thursday) for 6 weeks (maximum of 49 days) 
administered between 45 and 60 minutes before the start of RT. 
Rest 
After 6 weeks (30 fractions) of RT and temozolomide, subjects will have a 28-day rest.  
Post-Radiation Temozolomide Treatment Period 
During the post-radiation temozolomide treatment period subjects will receive: 


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All subjects will receive:  28-day oral temozolomide (150 mg/m2 first cycle and 200 mg/m2 all 
subsequent cycles as tolerated) administered on Day 1-5 (Monday through Friday) of each 28-
day cycle. 
Controls:  Will receive oral temozolomide per the standard of care. 
Subjects randomized to TSC:  will receive TSC 1.5 mg/kg, 1.5 to 2 hours before each 
temozolomide dose during the daytime, for 3 days during the first week of each 28-day cycle 
(Days 1, 3, 5: e.g. Monday, Wednesday, Friday, or other schedule that supplies at minimum 3 
TSC doses per week).  Long-acting antiemetics may be administered prior to daytime 
temozolomide dosing on Days 1, 3, 5.  
The study design is shown in Table 5. 
 
 


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Table 5.  Study Design 
 
Diagnosis / Screening 
≤ 4 weeks prior to randomization (minimum 21 days) 
 
• Suspected brain tumor  
• Diagnostic Brain MRI 
• Brain biopsy 
• Histologic confirmation of GBM (locally reviewed) 
• Subject treatment plan includes RT and temozolomide 
• Informed consent 
• Demographics, medical history, physical exam, vitals, ECG, lab, KPS, pregnancy test 
 
Baseline / Stratification / Randomization (maximum 14 days) 
• Pre treatment, post 49iopsy MRI ≤ 7 days prior to randomization 
• Perform any remaining tests or repeat of tests ≤ 7 days prior to randomization 
• Randomization prior to treatment 
• Stratification 
• Age ≤ 60, > 60 
• Multiple tumors versus Single tumors 
• IDH status (IDH-mutant, IDH-wt) 
 
RT Treatment 
• RT treatment recommended to begin >3 but ≤5 weeks after biopsy 
• Treatment with SOC RT/temozolomide ± TSC for 6 weeks 
 
Rest 
• No treatment for 4 weeks 
 
Week 10 
• 10 week MRI (4weeks after the conclusion of RT at week 6) per BTIP to be used as 
the Baseline comparison scan for assessment of PFS and ORR per mRANO criteria  
 
Chemotherapy Only Treatment 
• Treatment with SOC temozolomide for six 28-day cycles ± TSC 
• TTF per Investigator SOC 
 
Follow Up 
• Follow subject until death 
 


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3.2 
Study Population 
 Subject Population 
Newly diagnosed GBM biopsy-only subjects who meet all inclusion and exclusion criteria. 
 Inclusion Criteria 
1. Male or female subjects who are at least 18 to 70 years of age 
2. Have histologically confirmed GBM   
3. The only surgical consideration is biopsy. Subjects who had gross total resection, partial 
resection and/or debulking are excluded. 
4. Measurable (>10mm x 10mm) contrast enhancing disease. 
5. Limited disturbance of tumor during biopsy  
6. Surgical and pathology reports that document surgery was limted to biopsy and histologic 
confirmation 
7. Life expectancy of at least 3 months.   
8. Subjects must have a Karnofsky score (KPS) of ≥ 60 at Screening. 
9. Glucocorticoid therapy allowed.   
10. Tumor Treatment Field (TT Fields) therapy allowed. 
11. If female, the subject must have a negative serum or urine pregnancy test at Screening unless 
meeting non-productive potential criteria. 
12. Subjects must have hematologic and renal functions as specified: Absolute neutrophil count 
≥ 1500/mm3, platelets ≥ 100,000/mm3, Hgb ≥ 9.0g/dL, creatinine ≤ 1.7mg/dL, total bilirubin 
≤ 1.5mg/dL, blood urea nitrogen (BUN) within 2 times the upper limit of normal, 
transaminases ≤ 4 times above the upper limits of the institutional norm. 
13. The subject or subject’s medical power of attorney has provided written consent to 
participate in this study. 
 Exclusion Criteria 
Subjects are not eligible if they meet any of the following criteria: 
 
1. Subjects who had gross total tumor resection, partial resection, and/or debulking surgery. 
2. Subjects must not have had prior RT, chemotherapy (including Gliadel wafer), 
immunotherapy or therapy with a biologic agent, or hormonal therapy.   
3. Subject who is pregnant or lactating. 
4. Subject with a serious concurrent infection or medical illness that would jeopardize the 
ability of the subject to receive study treatment with reasonable safety. 
5. Subject who cannot undergo MRI. 
6. Subject receiving concurrent chemotherapeutics or investigational agents within 30 days of 
study entry, including gliadel wafers or gliasite application. 
7. Subjects with other uncontrolled medical conditions, e.g. myocardial infarction, 
cerebrovascular accident, diabetes or hypertension 


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8. Subjects diagnosed with another malignancy within 3 years prior to study start with the 
exception of adequately treated basal cell carcinoma, squamous cell carcinoma, non-
melanomatous skin cancer or carcinoma in situ of the uterine cervix 
9. CTCAE Version 4, Grade 4 non-hematological toxicity (except for alopecia, nausea, 
vomiting). 
 Women of non-reproductive potential 
A woman is of non-reproductive potential if the woman meets 1 of the following conditions:  
• At least 2 years post-menopausal 
• Hysterectomy 
• Bilateral oophorectomy 
• Tubal ligation 
 Acceptable Methods of Birth Control 
Women of reproductive potential must use a double method of birth control through 30 days 
after the last dose of test article (Week 34) or temozolomide.  Subjects must use 2 of the 
following acceptable methods of birth control as applicable:  
• Oral, transdermal, or implanted hormonal contraceptives at a stable dose for at least 2 
months prior to Randomization  
• Intrauterine device 
• Diaphragm with spermicide 
• Male condom 
 
The concomitant medication and/or medical history documentation including that recorded on 
the eCRF for females of reproductive potential should support contraceptive usage, as applicable.   
3.3 
Withdrawal of Subjects 
 Stopping Rules 
The Data Safety Monitoring Board will examine the safety profile of TSC at prescribed time 
points during the trial per the DSMB charter. 
 
In addition, if > 2 of first 10 subjects in the randomized portion of the trial are unable to 
complete > 75% of the RT due to toxicity related to the addition of TSC to RT and 
temozolomide the study will be stopped and the overall safety of TSC added to RT and 
temozolomide re-assessed. 
 Criteria for Early Withdrawal  
The following events are considered sufficient reason to discontinue a subject from the study: 
• Subjects are free to withdraw from the study at any time, for any reason, and without 
prejudice.  


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• The subject is non-compliant. 
• The subject experienced an adverse event (AE) that in the investigator’s opinion precludes 
continued participation. 
• The subject incurred a significant protocol violation that constitutes a safety hazard or 
significantly confounds the interpretation of the data from that subject.  
• At the Sponsor’s request. 
• The study is terminated. 
 Procedures for Discontinuation 
The Sponsor’s Medical Officer or designee will be notified of the discontinuation of any subject 
as soon as feasible, either prior to or after the subject discontinues.  For subjects that withdraw, 
the Follow-up Visit assessments should be completed.  The reason for discontinuation must be 
recorded in the case report form (CRF).  If the subject discontinues due to an AE, the 
investigator should follow the AE until resolution or until the investigator and Sponsor 
(designated Medical Monitor) agree that no further follow-up is warranted.  If protocol treatment 
is discontinued, follow-up and data collection will continue as specified in the protocol, if 
possible. 
3.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants. Minimal information 
includes demography, screen failure details and eligibility criteria. 
 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Lab values may be reassessed during the study defined screening period without 
being considered as rescreening.  Rescreened participants should be assigned the same 
participant number as for the initial screening. 
 Subjects Lost to Follow-up 
The investigator will attempt to contact any subject that fails to return in order to evaluate the 
reason the subject has not returned and to obtain follow-up safety information.  All attempts to 
contact the subject should be documented via registered letter with return receipt.  
 Replacement of Subjects 
Only randomized subjects who did not receive any TSC and did not receive a RT session will be 
replaced.  Subjects who have received TSC and/or at least 1 session of RT will not be replaced. 


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6.1 
Populations 
The intent-to-treat (ITT) population will include all subjects randomized.  The primary analysis 
will be conducted on the ITT population, with subjects grouped according to randomized 
treatment, regardless of treatment actually received. 
 
The safety population will include all subjects who received any treatment on study.  Subjects in 
the safety analyses will be grouped according to treatment actually received.  
6.2 
Subject Disposition 
At the end of the study, a disposition or reason for discontinuation will be recorded for all 
enrolled subjects.  The frequency with which subjects leave the study for a given reason will be 
summarized descriptively by treatment group.  Continued treatment with TSC beyond that will 
not be offered. 
6.3 
Demographics and Baseline Characteristics 
Demographic characteristics at baseline such as age, race, and gender will be summarized 
descriptively. 
6.4 
Efficacy Analysis 
 Primary Efficacy Analysis 
Overall Survival 
The primary objective of this study is to determine whether TSC in combination with SOC RT 
and temozolomide chemotherapy improves overall survival in newly diagnosed GBM biopsy-
only subjects relative to  SOC alone. Overall survival will be calculated from randomization to 
the time of death from any cause.  Subjects with unknown survival status will be either censored 
administratively at the time of the primary analysis or the time of last known survival status will 
be used.   
Overall survival will be estimated in time-to-event fashion using Kaplan-Meier methods.  
Survival rates at 6, 12, 18 and 24 months will also be calculated with corresponding 95% 
confidence intervals.  Median OS will be calculated for each treatment arm.   
Analysis of stratification factors will include: 
• Age ≤ 60, > 60 
• Multiple or single tumor(s) 
• IDH status (IDH-mutant, IDH-wt) 
 
 


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Secondary Efficacy Analysis 
Progression Free Surival (PFS) 
Confirmed PFS will be analyzed similarly to OS in time to event fashion.  Assessments will be 
as defined by RANO and mRANO criteria.   
For RANO analysis, the pre treatment, post biospy MRI ≤ 7 days prior to randomization will be 
considered the Baseline. To determine progression events, follow-up MRI scans performed at 
Weeks 10, 18, 26, 34, 42, 50, 52, 58, 66, 74, 82, 90, 98, 106 will be compared to the pre-
treatment MRI.  RANO does not require confirmation of progression, therefore the date of the 
event is the date of the first instance of PD. 
For mRANO analysis, the Week 10 MRI scan will be considered the Baseline.To determine 
progression events, follow-up MRI scans performed at Weeks 18, 26, 34, 42, 50, 52, 58, 66, 74, 
82, 90, 98, 106 will be compared to the Week 10 scan.  In order to be considered a true 
progression event, the progression must be confirmed per the mRANO criteria.  The date of the 
event is the date of the first instance of PD (preliminary PD).  Follow-up MRIs in accordance 
with mRANO to separate true progression from pseudoprogression will be done since 
pseudoprogression was evident in the Phase 2 trial, but not accounted for in PFS determination. 
Objective Response Rate (ORR) 
Durable objective response rate (CR and PR) will be estimated via radiological assessment using 
RANO and mRANO 
For RANO analysis, the pre-RT and pre-temozolomide MRI will be considered the Baseline. For 
mRANO analysis, the Week 10 MRI scan will be considered the Baseline. Both RANO and 
mRANO require confirmation of response. To be considered a true response, the response must 
be maintained until the next MRI scan at least 4 weeks later. The first instance of reponse is 
considered confirmed, or durable, and would represent the date of response. 
The secondary endpoints of PFS and ORR will be evaluated if the primary endpoint is 
statistically significant.  A Bonferroni correction will be included in the analysis of PFS and 
ORR to control the overall false positive rate. Improvements in PFS and ORR will be considered 
statistically significant if the p-value in a 2-sided test is less than 0.025.  Patient Reported 
Outcome (PRO) will not be considered an endpoint for product labeling. 
Karnofsky Performance Scale (KPS) 
Functional status will be evaluated using KPS. 
Quality of Life (QOL) –European Quality of Life Questionnaire (EQ-5D-5L) 
EQ-5D-5L is a standardized, non-disease specific instrument for describing health status 
(Herdman et al. 2011).  EQ-5D system consists of two parts: the EQ-5D descriptive system and 
the visual analog scale (VAS).  The EQ-5D descriptive system includes 5 dimensions of health 
(mobility, self-care, usual activities, pain/discomfort and anxiety/depression).  Each dimension 


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comprises 5 levels (no problems, slight problems, moderate problems, severe problems and 
unable to/extreme problems).  The VAS records the respondents’ self-rated health status on a 
vertical graduated (0-100) VAS.  The EQ-5D data will be scored as described by McDowell and 
Newell (1996).  A higher score represents a better health status.  QOL data will be analyzed and 
presented descriptively by treatment arm. 
 
Corticosteroid, Anticonvulsant and Chemotherapy for Recurrent Glioma 
Concomitant use of corticosteroids, anticonvulsants, and other chemotherapy agents as part of 
the subject’s treatment plan will be documented throughout the study. Response will also be 
evaluated by stable or decreasing concomitant corticosteroid use and chemotherapy agents 
needed as part of the subject’s treatment plan for recurrent glioma.  These data will be analyzed 
and presented descriptively. 
 
Adverse Events of Special Interest 
Given that TSC may positively impact several adverse events common to the standard of care, 
appearance and changes in leukopenia, thrombocytopenia and peripheral neuropathy will be 
analyzed and presented descriptively and will be graded according to CTCAE. 
6.5 
Safety Analysis 
No formal statistical hypothesis testing will be performed with regard to safety variables. The 
safety assessments will include the collection of adverse events, physical exam, concomitant 
medication usage, vital signs, 12-lead ECG, and clinical laboratory.    
 
Adverse Events 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be used for AE reporting.  Adverse events will be 
coded using the MedDRA coding dictionary. Summaries of treatment emergent adverse events 
will be reported overall, by severity and by relationship to study drug. Incidence rates will be 
reported by body system, organ class and preferred term by treatment arm. Progression of 
disease including death will not be considered an AE. AEs that occur beyond 30-days after the 
last dose of test article (Week 34) will not be collected as part of the safety database.  
 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or the study, or that caused the 
participant to discontinue the study treatment. 
Time Period and Frequency for Collecting AE and SAE Information  
All AEs will be collected from the start of study treatment until 30-days after the last dose of test 
article, as well as at the time points specified in the Schedule of Events.  SAEs will be collected 
from the start of treatment until the last follow-up visit.   
 


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Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded as pre-existing conditions on the Medical History section of the case 
report form (CRF). 
 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
 
Investigators are not obligated to actively seek AE or SAE information from former study 
participants. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study treatment or study participation, the investigator must promptly notify the 
sponsor. 
Method of Detecting AE and SAE 
Care will be taken not to introduce bias when detecting an AE and/or SAE. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.  
Follow-up of AE and SAE 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest will be followed 
until resolution, stabilization, until the event is otherwise explained, or the participant is lost to 
follow-up.  
Regulatory Reporting Requirements for SAE 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
treatment under clinical investigation are met. 
 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
relevant regulatory agencies about the safety of a study treatment under clinical investigation. 
The sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators. 
 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAE) from the sponsor will file it along with the 
Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.