A Randomized, Double-blind, Clinical Trial of a Hemp-Derived, High Cannabidiol Product for Anxiety in Glioblastoma Patients
Phase: PHASE2
Conditions: Glioblastoma
Sponsor: Mclean Hospital

Official Title: A Clinical Trial of a Hemp-Derived, High-Cannabidiol Product for Anxiety in 
Glioblastoma Patients 
 
IRB Protocol Title: A Randomized, Double-Blind, Clinical Trial of a Hemp-Derived, High 
Cannabidiol Product for Anxiety in Glioblastoma Patients 
 
NCT Number: NCT05753007 
 
Document Date: August 1, 2024 

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A Randomized, Double-blind, Clinical Trial of a Hemp-Derived, High 
Cannabidiol Product for Anxiety in Glioblastoma Patients 
Protocol Number: 
V2.7 
Version Date: 
01AUG2024 
Investigational Product: 
Industrial hemp-derived ultra-high cannabidiol sublingual solution 
IND Number: 
160874 
Development Phase: 
Pilot 
Funding Organization: 
Sundry Funds/Department 
Principal Investigators: 
Nicholas Butowski MD 
University of California San Francisco 
San Francisco, CA 94143 
Telephone:  415-353-2966 
Fax:  415-353-2167 
Nicholas. Butowski@ucsf.edu 
 
Staci A. Gruber, Ph.D. 
McLean Hospital 
Harvard Medical School 
115 Mill Street 
Belmont, MA 02478 
Telephone: 617-855-2672 
Fax: 617-855-3713 
Coordinating Center: 
UCSF 
Statistician  
 
Dr. M. Kathryn Dahlgren 
McLean Hospital 
Harvard Medical School 
115 Mill Street 
Belmont, MA 02478 
Telephone: 617-855-2541 
Fax: 617-855-3713 
dahlgren@mclean.harvard.edu 
 
 

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Approval: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PI or Sponsor Signature (Name and Title)  
 
 
 
 
 
 
 
Date 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time.  The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.   
 
 
 
 
 
 
 
 

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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties include 
ensuring the safety of the study subjects enrolled under my supervision and providing Sundry 
Funds/Department with complete and timely information, as outlined in the protocol.  It is 
understood that all information pertaining to the study will be held strictly confidential and that 
this confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of the 
study staff and myself, I agree to maintain the procedures required to carry out the study in 
accordance with accepted GCP principles and to abide by the terms of this protocol. 
 
Protocol Number: V2.7 
 
Protocol Title:  An Open-Label Clinical Trial of a Hemp-Derived, High Cannabidiol Product for 
Anxiety in Glioblastoma Patients 
 
 
Protocol Date:  01AUG24 
 
 
 
 
Investigator Signature  
 
Date 
 
Print Name and Title 
Site # 
 
 
Site Name 
 
Address 
 
 
 
 
 
 
 
Phone Number 
 
 
 

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Table of Contents 
1 
BACKGROUND ......................................................................................................................... 13 
2 
STUDY RATIONALE ................................................................................................................. 15 
3 
RISK / BENEFIT ASSESSMENT ........................................................................................................ 15 
3.1.1    Risks Associated with Clinical Assessment/Rating Scales ......................................................... 15 
3.1.2    CBD Administration .................................................................................................................. 15 
3.1.3    Potential Benefits ..................................................................................................................... 16 
4 
STUDY OBJECTIVES ............................................................................................................... 17 
4.1    PRIMARY OBJECTIVE ......................................................................................................................... 17 
4.2    SECONDARY OBJECTIVES .......................................................................................................................... 17 
4.3    EXPLORATORY OBJECTIVES ....................................................................................................................... 17 
5 
STUDY OVERVIEW ........................................................................................................................ 17 
5.1    SCREENING (IN-PERSON) ......................................................................................................................... 18 
5.2   BASELINE VISIT (0-2 WEEKS AFTER STARTING RADIATION; IN-PERSON) .............................................................. 19 
5.3    TREATMENT PERIOD (WEEKS 0-8; REMOTE) ................................................................................................ 20 
5.4    END OF STUDY (IN-PERSON) ..................................................................................................................... 20 
6 
CRITERIA FOR EVALUATION ............................................................................................... 21 
6.1    PRIMARY ENDPOINT .......................................................................................................................... 21 
6.2    SECONDARY AND EXPLORATORY ENDPOINTS ................................................................................... 21 
6.3    SAFETY EVALUATIONS ...................................................................................................................... 21 
7 
SUBJECT SELECTION ............................................................................................................. 22 
7.1    STUDY POPULATION .......................................................................................................................... 22 
7.2    INCLUSION CRITERIA ......................................................................................................................... 22 
7.3    EXCLUSION CRITERIA ........................................................................................................................ 22 
8 
CONCURRENT MEDICATIONS .............................................................................................. 24 
ALLOWED MEDICATIONS AND TREATMENTS ........................................................................................................ 24 
9 
STUDY TREATMENTS ............................................................................................................. 25 
9.1    METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ........................................................................... 25 
9.2    PACKAGING AND LABELING ...................................................................................................................... 25 
9.3   SUPPLY OF STUDY DRUG AT THE SITE .......................................................................................................... 26 
9.3.1    Dosage/Dosage Regimen ......................................................................................................... 26 
9.3.2 
Dispensing ............................................................................................................................. 26 
9.3.3    Administration Instructions ...................................................................................................... 26 
9.3.4    Storage ..................................................................................................................................... 26 
9.4    STUDY DRUG ACCOUNTABILITY ....................................................................................................... 26 
9.5    MEASURES OF TREATMENT COMPLIANCE ......................................................................................... 27 
10 
STUDY PROCEDURES AND GUIDELINES ............................................................................ 27 
10.1    CLINICAL ASSESSMENTS ................................................................................................................. 27 
10.1.1    Concomitant Medications ...................................................................................................... 27 
10.1.2    Demographics ........................................................................................................................ 27 
10.1.3    Medical History ...................................................................................................................... 27 
10.1.4    Adverse Events ....................................................................................................................... 27 
10.2    CLINICAL LABORATORY MEASUREMENTS ...................................................................................... 27 

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10.2.1    Pregnancy Test ....................................................................................................................... 27 
10.2.2    Urinalysis ............................................................................................................................... 27 
10.3.3    Cannabinoid and endocannabinoid analysis .......................................................................... 28 
11 
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ..................................... 28 
11.1    ADVERSE EVENTS ........................................................................................................................... 28 
11.2    AE SEVERITY ....................................................................................................................................... 28 
11.3    AE RELATIONSHIP TO STUDY DRUG ......................................................................................................... 29 
11.4    SERIOUS ADVERSE EXPERIENCES (SAE) ......................................................................................... 29 
11.4.1    Serious Adverse Experience Reporting .................................................................................. 30 
12 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS ................................................ 30 
12.1   EARLY DISCONTINUATION OF STUDY DRUG .................................................................................... 30 
12.2    WITHDRAWAL OF SUBJECTS FROM THE STUDY ........................................................................................... 31 
12.3    REPLACEMENT OF SUBJECTS ................................................................................................................... 31 
13 
PROTOCOL VIOLATIONS ....................................................................................................... 32 
14 
DATA AND SAFETY MONITORING ....................................................................................... 32 
15 
STATISTICAL METHODS AND CONSIDERATIONS ........................................................... 32 
15.1    DESCRIPTIVE STATISTICS ........................................................................................................................ 32 
15.2    ANALYSIS OF PRIMARY AND SECONDARY ENDPOINTS .................................................................................. 32 
15.3    ANALYSIS OF SECONDARY ENDPOINTS ........................................................................................... 33 
15.4    ANALYSIS OF EXPLORATORY ENDPOINT ..................................................................................................... 33 
15.5    SAMPLE SIZE AND RANDOMIZATION ........................................................................................................ 33 
15.6    DATA SETS ANALYZED ................................................................................................................... 35 
16 
DATA COLLECTION, RETENTION AND MONITORING .................................................... 35 
16.1    DATA COLLECTION INSTRUMENTS .................................................................................................. 35 
16.2    DATA MANAGEMENT PROCEDURES ................................................................................................ 35 
16.3    DATA QUALITY CONTROL AND REPORTING .................................................................................... 35 
16.4    ARCHIVAL OF DATA ........................................................................................................................ 35 
16.5    AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS .................................................... 36 
16.6    MONITORING ................................................................................................................................... 36 
16.7    SUBJECT CONFIDENTIALITY ............................................................................................................ 36 
17 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ................................ 36 
17.1    INSTITUTIONAL REVIEW BOARDS AND INDEPENDENT ETHICS COMMITTEES ................................... 36 
17.2    INFORMED CONSENT FORM ............................................................................................................. 37 
17.3    INVESTIGATOR RESPONSIBILITIES ................................................................................................... 37 
I. 
APENDICES ................................................................................................................................... 42 
APPENDIX 1. SUICIDALITY POLICY FOR SUBJECTS WITH SUICIDAL IDEATION ................................................................. 43 
SUICIDALITY ASSESSMENT .................................................................................................................... 44 
RISK ASSESSMENT AND SAFETY PLANNING GUIDELINES ..................................................................... 45 
APPENDIX 2. DATA AND SAFETY MONITORING PLAN FOR A PHASE II OR III INSTITUTIONAL TRIAL .................................. 48 
A.2.1    Oversight and Monitoring Plan ................................................................................................ 48 
A.2.2   Monitoring and Reporting Guidelines ....................................................................................... 48 
A.2.3    Review and Oversight Requirements ........................................................................................ 49 
APPENDIX 3. RESEARCH BLOOD PROCEDURES FOR COLLECTING PLASMA FOR CANNABINOID,  
ENDOCANNABINOID AND INFLAMMATORY COMPONENT (PLEX-12 PANEL) ANALYSIS ................................ 51 
 

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LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BAI 
Beck Anxiety Inventory 
BUN 
blood urea nitrogen 
CBD 
Cannabidiol 
CFR 
Code of Federal Regulations 
CRF 
case report form 
CTCAE 
Common terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
DTI 
Diffusion Tensor Imaging 
EORTC 
European Organization for Research and Treatment of Cancer 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
IRB 
Institutional Review Board 
IV 
intravenous 
LDH 
lactate dehydrogenase 
MRI 
Magnetic Resonance Imaging 
OASIS 
Overall Anxiety Severity and Impairment Scale 
QOL 
Quality of Life 
PI 
Principal Investigator 
SAE 
serious adverse experience 
SOC 
Standard of Care 
THC 
Delta-9-Tetrahydrocannabinol 

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PROTOCOL SYNOPSIS 
TITLE 
An Open-Label Clinical Trial of a Hemp-Derived, High Cannabidiol 
Product for Anxiety in Glioblastoma Patients 
FUNDING 
ORGANIZATION 
Sundry Funds/Department 
NUMBER OF SITES 
1 
RATIONALE 
The proposed investigation will be the first of its kind to conduct a clinical 
trial of an industrial hemp-derived product in patients with glioblastoma. 
Despite the recent interest in Medicinal Cannabis and cannabinoid-based 
products, the availability of hemp-derived products in all 50 states, and 
anecdotal evidence suggesting that hemp-derived products may have a 
profound anxiolytic effect, no studies have conducted a clinical trial of a 
hemp-derived product in these patients despite their reported levels of 
anxiety. The recent passage of the Farm Bill of 2018 has resulted in the 
exclusion of industrial hemp-derived products (THC content <0.3% by 
weight) from the Controlled Substances Act (CSA). Accordingly, it is now 
possible to conduct clinical trials using industrial hemp-derived CBD 
products, which many thousands of consumers have purchased in recent 
years. As such, we will assess a proprietary hemp-derived full spectrum 
product formulated by Dr. Gruber; the custom formulation contains 
approximately 250 mg/ml of CBD and 1.8 mg/ml THC, along with several 
other cannabinoids. This investigation will provide information regarding the 
potential efficacy of an industrial hemp-derived CBD product for anxiety in 
this population, as well as provide information on the potential for a high-
CBD product to impact quality of life ratings and tumor progression. 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled study 
designed to examine the impact of a custom-formulated, high CBD 
product compared to standard of care plus placebo (SOC) in newly 
diagnosed glioblastoma patients undergoing chemoradiation therapy. 
PRIMARY 
OBJECTIVE 
To assess clinical ratings of anxiety (using BAI and OASIS scales) in 
individuals 
with 
newly 
diagnosed 
glioblastoma 
undergoing 
chemoradiation therapy pre- and post-CBD treatment compared to those 
receiving placebo.   
 

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SECONDARY  
 
and  
 
 
 
 
 
EXPLORATORY 
OBJECTIVES 
 
1) To assess pre and post-CBD treatment ratings of pain in BPI, VAS, 
PDS, PDI scales among newly diagnosed glioblastoma undergoing 
chemoradiation therapy compared to the SOC group. 
 
2) To assess pre- and post-CBD treatment ratings of quality-of-life in 
individuals with newly diagnosed glioblastoma undergoing chemoradiation 
therapy using QLQ-C30 and BN-20 instruments, compared to the SOC 
group. 
 
1) Exploratory Objective 1.  To examine pre- and post-CBD treatment 
measures of tumor progression, quantified using neuroimaging 
techniques including structural magnetic resonance (MRI) and diffusion 
tensor imaging (DTI), and perfusion imaging in individuals with newly 
diagnosed glioblastoma compared to the SOC group. 
2) Exploratory Objective 2. To examine pre- and post-CBD treatment 
measures of inflammation using the 12-plex panel that includes: IL-1ß, 
IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IFN-α2, IFN-γ, 
and TNF-α  
3) Exploratory Objective 3. To compare time-to-progression, progression 
free survival,  and overall survival rates between the CBD+SOC and 
SOC groups. 
4) Exploratory Objective 4. To assess the utilization of the MyStori 
Mobile app by patients and compare adverse events and symptoms 
reported in the app to those reported during the in-person patient visit 
NUMBER OF 
SUBJECTS 
36 Total subjects: 
    24 Subjects will be enrolled in the study treatment group (CBD+SOC) 
    12 subjects will be enrolled in the standard of care plus placebo (SOC) 
group 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria 
1. 
Male or female ≥ 18 years of age 
2. 
Documentation of newly diagnosed glioblastoma, evidenced by 
neuropathology report and based on WHO 2021 classification (IDH-
mutant glioblastoma grade 4), and who are to undergo SOC (~ 6 
weeks of treatment) with radiation and temozolomide (patients using 
Optune may be included) 
3. 
Written informed consent obtained from subject or subject’s legal 
representative and ability for subject to comply with the requirements 
of the study 
4. 
Fluent in English  
5. 
Scores a minimum of 16 on the Beck Anxiety Inventory (BAI) OR a 
minimum of 8 on the Overall Anxiety Severity and Impairment Scale 
(OASIS) at the screening visit. Re-testing is allowed if it is within the 
stipulated windows (see section 5.1)  

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6. 
Stable medication/psychotherapy regimens for at least 1 month prior 
to starting the study (excluding new glioblastoma treatment-related 
medications or radiation) 
7. 
KPS of 60 or higher 
 
 
Exclusion Criteria 
1. 
Pregnant, breastfeeding, or unwilling to practice birth control during 
participation in the study. 
2. 
Presence of a condition or abnormality that in the opinion of the 
Investigators would compromise the safety of the patient or the quality 
of the data. 
3. 
Current substance use disorder, psychotic disorder, bipolar disorder, or 
eating disorder 
4. 
Current use of recreational cannabis, medical cannabis, or hemp-
derived cannabinoid products more frequently than 1x/month; positive 
urine THC test 
5. 
Presence of a serious or unstable medical illness, including liver, 
kidney, or cardiovascular disease. The following laboratories will be 
performed used to confirm normal function of systems within 28 days 
of day 1 of start study treatment: 
a. Creatinine >1.5 x ULN (Cockroft and Gault) 
b. AST > 3.0 x ULN 
c. ALT > 3.0 ULN 
d. Total bilirubin > 3.0 x ULN 
e. Platelet count outside of normal limits 
f. ANC outside of normal limits 
6. 
Current use of valproate (due to potential for drug-drug interactions) 
7. 
Receiving additional, concurrent, active therapy (including 
investigational) for glioblastoma other than standard of care.  
8. 
Have received any prior treatment for glioma including but not limited 
to:  
-Prolifeprospan 20 with carmustine wafer 
-Prior intracerebral, intratumoral, or cerebral spinal fluid (CSF) agent 
-Prior radiation treatment for glioblastoma or lower-grade glioma 
-Prior chemotherapy or immunotherapy for glioblastoma or lower-
grade glioma  
9. 
Contraindication to MRI such as non-MR conditional medical devices 
or ferrous retained foreign bodies. 

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10. Additionally, concomitant medications will be assessed on a case-by-
case basis with the study physician;  
a. 
participants will be excluded if they are taking strong inhibitors or 
inducers of CYP3A4 (e.g. fluconazole, fluoxetine, fluvoxamine, 
ticlopidine, St. John’s Wort, etc.), CYP2C19 (e.g. ketoconazole, 
erythromycin, etc.), or CYP2D6 (e.g. paroxetine, buproprion, 
quinidine, ritonavir, glutethimide, etc.).   
b. 
In addition, participants will be excluded if they are taking blood 
thinners (e.g. warfarin, ticlopidine, rivaroxaban, ticagrelor, 
apixaban), 
carbamazepine, 
oxcarbazepine, 
phenytoin, 
fosphenytoin, phenobarbital, primidone, clobazam, lamotrigine, 
zonisamide, dexamethasone, dronabinol, or dulcolax.  
i. It is recognized that patients may require dexamethasone once on 
clinical trial. If so, they will not be excluded at that point. 
However, the dose needs to be <4mg at the start of the trial 
 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Subjects in both groups will self-administer 1ml of study product 
sublingually two times daily (BID) for 8 weeks; this corresponds to 
approximately 250mg of CBD per dose (500mg/day). After an efficacy 
evaluation after the 9th subject has completed their 8 week trial, will be 
determine whether dose will escalate to a total of 750mg/day 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be on study for up to 24 months 
    Screening: up to 28 days 
    Treatment: up to 8 weeks 
    Follow up: survival follow-ups (via chart review) will occur at 3 months, 
6 months, 12 months, and 24 months post-baseline 
CONCOMMITANT 
MEDICATIONS 
Concomitant medications will be assessed on a case-by-case basis with the 
study physician; participants will be excluded if they are taking strong 
inhibitors or inducers of CYP3A4 (e.g. fluconazole, fluoxetine, fluvoxamine, 
ticlopidine, St. John’s Wort, etc.), CYP2C19 (e.g. ketoconazole, 
erythromycin, etc.), or CYP2D6 (e.g. paroxetine, buproprion, quinidine, 
ritonavir, glutethimide, etc.).  
 
In addition, participants will be excluded if they are taking blood thinners 
(e.g. 
warfarin, 
ticlopidine, 
rivaroxaban, 
ticagrelor, 
apixaban), 
carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, 
primidone, clobazam, lamotrigine, zonisamide, dexamethasone <4mg, 
dronabinol, or Dulcolax.  
 
Dosing schedules may be adjusted in order to offset CBD administration with 
concomitant medications to decrease the likelihood of any drug-drug 
interactions. Subjects must have been on stable medication/psychotherapy 
regimens for at least 1 months prior to starting the study (excluding new 
glioblastoma treatment-related medications or radiation). 

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EFFICACY 
EVALUATIONS 
Clinical response will be evaluated after the 9th subject has completed their 8 
week trial.  
If no clinical improvement is observed based on a review of clinical scales, a 
dose escalation will be considered to a total of 750mg CBD per day (1ml 
TID).  
Clinical improvement is defined as a 15% reduction in BAI scores compared 
to baseline.  
PRIMARY 
ENDPOINT 
• 
Reduction in Anxiety scales (BAI, OASIS) 
 
SECONDARY 
ENDPOINTS 
• 
Improvement in Quality of life (QLQ-C30 and BN20) scores.   
• 
Improvement in Pain (BPI, VAS, PDS, PDI) scales 
• 
Quantification of tumor change/progression using structural magnetic 
resonance (MRI), diffusion tensor imaging (DTI), and perfusion 
imaging measures 
OTHER 
EVALUATIONS 
• 
Other clinical rating scales will be completed which assess other 
domains of clinical state (BDI), sleep (PSQI), and treatment  
expectancy questionnaire  
• 
Blood samples will be analyzed to measure cannabinoid levels as well 
as inflammatory markers. 
• 
For research subjects that agree to participate in the optional portion of 
the study, MyStori App will be used to compare symptoms reported at 
the time of visit to those logged into the app  
 
SAFETY 
EVALUATIONS 
Adverse events will be continuously monitored for all subjects. 
Subjects will be evaluated at screening/baseline, 1 week, 2 weeks, 4 weeks, 
6 weeks and 8 weeks.  
PLANNED INTERIM 
ANALYSES  
We will assess clinical response after the first 9 patients have completed their 
8-week trial. If we do not see clinical improvement based on a review of 
clinical scales, subjective reports and performance, we will consider 
increasing the dose to a total of 750mg CBD per day (1ml TID). Clinical 
improvement using scales will be defined as a 15% reduction in BAI scores 
from baseline. An amendment would be submitted to the IRB for approval 
prior to adjusting the dose of CBD. 
STATISTICS 
Primary Analysis Plan 
We plan to enroll (i.e. assigned a treatment by randomization) 36 subjects: 
24 subjects will be randomized to the treatment arm. This group will receive 
high-CBD product along with standard of care (SOC) for chemoradiation 
(CBD+SOC group); 12 subjects will be assigned to receive SOC plus 
placebo (SOC group). 
We will analyze the population with an intention to treat (ITT) approach. The 
intent-to-treat (ITT) group is defined as all the subjects who have valid 
measurements at baseline and at least one post-baseline visit for at least one 
of the assessments while on study. The ITT group will be used for all 
analyses. ITT subjects will be analyzed according to the treatment to which 
the subject was randomized. 

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Standard demographic variables including age, sex and racial/ethnic origin 
will be summarized by treatment for all randomized subjects. 
Descriptive statistics for continuous variables will include the number of 
subjects (n), mean, median, standard deviation, minimum and maximum. For 
categorical variables, summaries will include counts of subjects and 
percentages. Percentages will be rounded to one decimal place.  
Rationale for Number 
of Subjects 
Power analyses indicate that, assuming a correlation coefficient of the 
outcome overtime of 0.5, a sample size of at least 12 individuals per group 
is required for 2x6 mixed model analyses to detect medium effect sizes 
(Cohen’s f=.35) at power 80% and alpha level 0.05. 
 

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1 
BACKGROUND 
Cannabis sativa has been used medically for a range of disorders for thousands of years, including 
anxiety. Cannabis is comprised of more than 100 phytocannabinoids; D9-tetrahydrocannabinol (Δ9-
THC) is the major psychoactive constituent of the plant, while cannabidiol (CBD) is a major non-
intoxicating constituent often touted for a variety of potential therapeutic benefits. Industrial hemp 
is a specific variety of the Cannabis sativa plant, which until recently was grown for industrial 
applications, such as textiles. Hemp-based cultivars have much lower concentrations of THC than 
cannabis cultivars, defined as THC levels of <0.3% by weight. In recent years, some hemp cultivars 
have been bred to produce particularly high concentrations of CBD with very low concentrations of 
THC, virtually eliminating the potential for intoxication. Extracts from these hemp cultivars are 
manufactured into a variety of oils, capsules, sprays, etc., available for legal sale in brick-and-mortar 
stores across the country as well as on the Internet. 
 
Previous studies have demonstrated CBD’s anxiolytic potential in both animals and humans, 
generally in acute-administration models. Fusar-Poli et al. (2009) demonstrated that 600 mg of CBD 
reduced anxiety in healthy subjects viewing fearful faces while undergoing functional magnetic 
resonance imaging (fMRI); the authors concluded that this effect was likely due to modulating the 
activation of limbic and paralimbic regions. This same group later reported that CBD alters 
subcortical prefrontal connectivity via the amygdala and anterior cingulate (Fusar-Poli et al. 2010). 
Additionally, in a model of experimentally induced anxiety in healthy subjects, Zuardi et al. (1993) 
found that 300mg of CBD attenuated anxiety, as did the anxiolytic drugs diazepam and ipsapirone. 
To induce anxiety, the authors used the simulated public speaking test (SPST), which involves a 
subject speaking in front of a video camera for several minutes while physiological correlates of 
anxiety are measured (including heart rate and blood pressure), and self-report scales are 
administered to measure subjective anxiety. This model has also been used to induce anxiety in 
patients with social anxiety disorder (SAD); Bergamaschi et al. (2011) demonstrated that 
pretreatment with a single dose of CBD results in an anxiolytic effect for SAD patients. This single 
dose (600mg) was sufficient to reduce subjective anxiety, cognitive impairment, and discomfort in 
SAD patients completing the SPST, compared to placebo, and reduced anxiety in the CBD-treated 
patients to a level similar to that of healthy controls. Crippa et al. (2011) confirmed CBD’s effects 
in SAD and further investigated the basis of CBD’s anxiolytic effect in SAD patients using 
neuroimaging. Relative to placebo, a single dose of CBD (400mg) was associated with significantly 
decreased subjective anxiety scores in SAD patients.  
 
These studies used non-plant-derived or plant-derived single extracted compounds (e.g. CBD 
isolate), rather than a full or broad spectrum product which may confer greater clinical effect since 
they contain multiple cannabinoids, terpenoids, and flavonoids; these full or broad spectrum 
products are more analogous to the products generally used in the ‘real world’. Recently, our group 
began the first ever clinical trial of a high-CBD full-spectrum compound for patients with anxiety. 
This trial, studied under IND #126898, examines the impact of a custom-formulated high-CBD, 
low-THC cannabis-derived sublingual solution on measures of anxiety, mood, quality of life, and 
cognition over a 4-week treatment period in individuals with moderate to severe anxiety. Data from 
the open-label phase of this study are extremely promising; analyses indicate that patients reported 
a 79.93% reduction in anxiety symptoms on the primary outcome measure, the Beck Anxiety 
Inventory (BAI), from the baseline to final visit. Patients also reported a 77.94% reduction in 
depression symptoms on the Beck Depression Inventory from the baseline to final visit. The study 
product is well-tolerated, with no serious adverse events occurring to date. 
 

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Glioblastoma (GBM) is incurable, and the most common malignant brain tumor among adults, with 
an estimated 5-year survival rate of >6% (Ostrum et al., 2016). Patients with brain tumors often 
suffer from comorbid conditions which impact their quality of life, including depression and anxiety 
(Pringle et al., 1999). Interestingly, patients with lower tumor grade have demonstrated a higher risk 
of neuropsychiatric conditions, specifically anxiety (Arnold et al., 2008). Despite this finding, only 
a percentage of patients report the use of conventional medication for anxiety or depression which 
may be the result of a failure to accurately diagnose the condition or inadequate assessment of brain 
tumor patients at clinical visits (Arnold et al, 2008). In a recent study, Schloss et al. (2021) reported 
that GBM patients who utilized a single daily dose of a 1:1 THC:CBD product for 12 weeks 
demonstrated improved sleep and quality of life. Accordingly, alternative treatments for anxiety are 
indicated.   
 
Interestingly, GBM tumors express both CB1 and CB2 receptors (Ellert-Miklaszewsk et al., 2013), 
with higher grade tumors expressing greater levels of CB2, suggesting that the endocannabinoid 
system may be implicated in GBM pathology. Recent preclinical work has demonstrated that 
exogenous cannabinoids may impact GBM tumor growth. Specifically, CBD has been shown to 
destroy GBM cells by inducing DNA binding of a modified nuclear factor kappa B (NF-kB) subunit 
and exhibited the best cytotoxic activity from a panel of non-intoxicating cannabinoids (Volmar et 
al., 2021). Interestingly, a study of an inhalable 985 mg broad-spectrum CBD product in mice 
resulted in inhibition of GBM tumor growth by regulating the dynamics of several important tumor 
signaling pathways (Khodadadi et al., 2021). Other cannabinoids such as cannabigerol (CBG) may 
also act as anti-tumor agents (Lah et al., 2021). Accordingly, a whole-plant, full-spectrum, high-
CBD product containing a range of cannabinoids, terpenoids and other compounds at doses similar 
to those previously used may confer clinical benefit in this population. 
 
1.1 MyStori App background 
Subjects living with brain tumors often experience a wide range of disease and treatment-related 
symptoms, as noted by Armstrong et al. (2016). Effectively managing these symptoms is crucial 
throughout the entire disease trajectory, as studies have shown that symptom burden at brain tumor 
diagnosis can predict important clinical outcomes such as overall survival (OS) and progression-
free survival (PFS) (Armstrong et al., 2013). 
Recognizing the significance of symptom management across various cancer types, experts in the 
field and relevant organizations have recommended the inclusion of a standardized set of core 
symptoms for routine assessment in oncology research and clinical care (Basch et al., 2013). It is 
worth noting that caregivers of brain tumor patients can also identify symptoms, and previous 
research has demonstrated a high level of agreement between patient and caregiver assessments 
regarding severe symptoms. However, discrepancies arise when comparing more subtle symptoms 
that may indicate patient function (Armstrong et al., 2012). 
To address these challenges, the MyStoriTM app was developed specifically for brain tumor patients 
and their caregivers to facilitate symptom management. Research conducted by Armstrong et al. 
(2021) has shown that providing caregivers and patients with user-friendly tools to track symptoms 
can help identify triggers and enhance communication with clinicians, thereby improving the 
effectiveness of clinical visits. This not only leads to better patient outcomes but also alleviates 
burden on caregivers and patients. 

Protocol Version 2.7 
 
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Protocol date: 01AUG24 
The purpose of including the MyStoriTM app in our study protocol is to compare the number and 
severity of symptoms recorded within the application by caregivers and patients with those reported 
during clinic visits (whether conducted remotely or in-person). This comparison will enable 
investigators and patients to more accurately monitor their symptoms and evaluate the safety of the 
investigational product. Moreover, it will allow us to assess the feasibility of implementing this 
application in future research studies to streamline reporting systems and reduce the burden on 
patients when providing self-reported information. 
 
2 
STUDY RATIONALE 
The proposed investigation will be the first of its kind to conduct a clinical trial of an industrial 
hemp-derived product in patients with glioblastoma. Despite the recent interest in Medicinal 
Cannabis and cannabinoid-based products, the availability of hemp-derived products in all 50 states, 
and anecdotal evidence suggesting that hemp-derived products may have a profound anxiolytic 
effect, no studies have conducted a clinical trial of a hemp-derived product in these patients despite 
their reported levels of anxiety. The recent passage of the Farm Bill of 2018 has resulted in the 
exclusion of industrial hemp-derived products (THC content <0.3% by weight) from the Controlled 
Substances Act (CSA). Accordingly, it is now possible to conduct clinical trials using industrial 
hemp-derived CBD products, which many thousands of consumers have purchased in recent years. 
As such, we will assess a proprietary hemp-derived full spectrum product formulated by Dr. Gruber; 
the custom formulation contains approximately 250 mg/ml of CBD and 1.8 mg/ml THC, along with 
several other cannabinoids. This investigation will provide information regarding the potential 
efficacy of an industrial hemp-derived CBD product for anxiety in this population, as well as provide 
information on the potential for a high-CBD product to impact quality of life ratings and tumor 
progression. 
 
 
3 
RISK / BENEFIT ASSESSMENT 
3.1.1    Risks Associated with Clinical Assessment/Rating Scales  
Although unlikely, it is possible that during the structured assessment or rating scales, subjects 
may become distressed when recalling periods of their lives or their current mood state. Subjects 
are informed that they can take a break and/or can choose to stop answering questions at any time. 
To mitigate any risks associated with the clinical ratings, clinical staff will be available to evaluate 
and advise the subject during study visits. 
 
3.1.2    CBD Administration 
CBD has been shown to have an extremely low side effect profile and since the total amount of THC 
will not exceed 0.3% by weight, we do not expect significant side effects or psychoactive effects. 
CBD is not a scheduled substance, and there is no risk of intoxication or addiction to CBD. As with 
any clinical trial, there are risks of experiencing side effects from the administration of CBD; these 
side effects are very rare. Epidiolex, the first and only FDA-approved CBD product developed for 
pediatric intractable seizure disorders, has dosing recommendations of up to 20 mg/kg/day; this dose 
has been shown to be reasonably well-tolerated. Cunha et al. (1980) reported no signs of toxicity or 
serious side effects; in this two-part, placebo-controlled, double-blind study, healthy volunteers 

Protocol Version 2.7 
 
Page 16 of 51 
Protocol date: 01AUG24 
were given 3 mg/kg of CBD or placebo per day for 30 days, and patients with epilepsy were given 
200-300mg CBD or placebo per day for 4.5 months. Other studies have reported no adverse effects 
of CBD in patients with Huntington’s disease, schizophrenia, and Parkinson’s disease after repeated 
administration (Consroe et al. 1991; Leweke et al. 2012; Zuardi et al. 2006 and 2009). Some reports 
of increased liver function tests (LFTs) have been reported following CBD administration; however, 
a recent industry-based investigation did not find evidence for increased LFTs (Kaufmann et al., 
2021). Dr. Gruber has conducted several clinical trials of whole plant, full spectrum high-CBD 
products, and no serious adverse events have been reported to date. Dr. Gruber has conducted 
several clinical trials of whole plant, full spectrum high-CBD products, and no serious adverse 
events have been reported to date. Subjects will have the opportunity to report adverse effects at 
their check-in visits via direct contact with the PI and study staff. This reporting will reduce the 
likelihood that subjects experience significant negative side effects for any significant period of 
time, and the Pis/study physicians will be reachable by page 24 hours a day 7 days a week. In 
addition, SOC includes a full laboratory panel concurrent with the screening visit, which will be 
reviewed prior to inclusion in the study; patients taking concomitant anticonvulsants will also 
complete LFT blood draws at baseline, 4, and 8 weeks.  
 
Sublingual solutions are unlikely to be viewed by the public as analogous to recreational smoked 
marijuana, thus decreasing the risk of the subject experiencing any potential negative appraisal 
arising from perceived notions associated with marijuana use while partaking in this study.  
 
The safety of CBD administration in pregnant women and fetuses is unknown. Female participants 
capable of child-bearing will be asked to provide a sample of urine before the study is begun and at 
each subsequent study visit in order to screen for pregnancy. If the pregnancy test is positive at any 
point during the study, the subject will be immediately disqualified and participation in the study 
will cease. Participation requires that the participant uses contraception methods (such as abstinence, 
diaphragm, condom, or an intrauterine device) to prevent pregnancy for the duration of the study. 
The participant will be asked to notify study staff immediately if she misses a period or thinks she 
might be pregnant. In this case, the participant may have to withdraw from the study. 
 
3.2    Potential Benefits 
There may be no direct benefits to the subjects; however, based on previous research, it is reasonable 
to expect that some subjects may experience an improvement in clinical state or quality of life related 
to a reduction in anxiety. 
 
It is reasonable to expect that this study will contribute to overall knowledge in this field and 
potentially provide benefits to society in general through improvements in treatment and 
management as a result of this increased level of understanding.  
 
Subjects are informed that there may be no direct benefit to them from participating in this 
study. Subjects may benefit from knowing that the results of this study may improve the future 
care of people prescribed medicinal marijuana, particularly those with anxiety. 

Protocol Version 2.7 
 
Page 17 of 51 
Protocol date: 01AUG24 
4 
STUDY OBJECTIVES 
4.1    Primary Objective 
1) To assess clinical ratings of anxiety (using BAI and OASIS scales) in individuals with 
newly diagnosed glioblastoma undergoing chemoradiation therapy pre- and post-CBD 
treatment compared to those receiving placebo.  
 
4.2    Secondary Objectives 
2) To assess pre and post-CBD treatment ratings of pain in BPI, VAS, PDS, PDI scales 
among newly diagnosed glioblastoma undergoing chemoradiation therapy, compared to 
the SOC group. 
 
3) To assess pre- and post-CBD treatment ratings of quality-of-life in individuals with newly 
diagnosed glioblastoma undergoing chemoradiation therapy using QLQ-C30 and BN-20 
instruments, compared to the SOC group.  
 
4.3    Exploratory Objectives 
5) To examine pre- and post-CBD treatment measures of tumor progression, quantified using 
neuroimaging techniques including structural magnetic resonance imaging (MRI), 
diffusion tensor imaging (DTI), and perfusion imaging compared to the SOC group. 
 
6) To examine pre- and post-CBD treatment measures of inflammation using the 12-plex 
panel that includes: IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IFN-α2, 
IFN-γ, and TNF-α  
 
 
7) To compare time-to-progression, progression free survival,  and overall survival rates 
between the CBD+SOC and SOC groups. 
8) To assess the utilization of the MyStori Mobile app by patients and compare adverse 
events and symptoms reported in the app to those reported during the in-person patient 
visit 
 
5 
STUDY OVERVIEW 
This study is a single center, randomized, double-blind, placebo-controlled study of an industrial 
hemp-derived high-cannabidiol product that will include 36 subjects with diagnosis of glioblastoma. 
Eligible participants will sign an informed consent form that describes all study procedures in detail. 
After being deemed eligible by the Principal Investigators or designee, subjects will be randomized 
on a 2:1 ratio. As such, 24 patients will be randomized to receive the high-CBD sublingual study 
product, and 12 patients will act as a control group, completing the same study measures and will 
continue to receive SOC as well as placebo. Subjects will complete study visits at the UCSF Neuro 
oncology Clinic (400 Parnassus Ave, 8th floor, San Francisco, CA) as well as remotely via REDCap. 
Following a preliminary screening process, and prior to any evaluation, all study subjects will be 
required to sign an informed consent form that describes all study procedures. The screen includes 
questions related to medical history, substance use history, demographics, and screening questions 
from the OASIS (see below) to determine whether the subject has anxiety. 

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Protocol Version 2.7 
 
Page 19 of 51 
Protocol date: 01AUG24 
who are on concomitant anticonvulsants will also submit a blood sample for liver function tests (see 
below). Additionally, a urine sample will be collected to measure the  presence of Cannabis in urine.  
 
Patients will complete a post-surgery MRI scan as part of their SOC that meets minimum consensus 
recommendations for a standardized brain tumor imaging protocol as described by Ellingson et al. 
(2015). Using this imaging, review will be performed by the PI or UCSF neuro-radiologist applying 
established response assessment criteria, RANO (Wen et al., 2010). The recommended protocol is 
as follows (though per the PI exceptions can be made due to technical limitations of some MRI 
scanners and or availability of sequences on certain MRI scanners): 
• 
2D axial and coronal diffusion weighted imaging (b = 1000) 
• 
3D axial T1 gradient recalled echo (eg MP-RAGE) 
• 
3D axial susceptibility weighted imaging (eg SWAN) 
• 
3D axial arterial spin labelling perfusion 
• 
2D axial T2 spin echo 
• 
Post-contrast 3D axial T1 gradient recalled echo (eg MP-RAGE) 
• 
Post-contrast 2D coronal T1 spin echo 
• 
Post-contrast sagittal T2 fluid-attenuated inversion recovery (FLAIR) 
 
5.2   Baseline visit (In-person) 
Following eligibility confirmation by the principal investigators or designee, the patient will 
perform a baseline visit within 2 weeks (14 days) of having initiated study therapy. The visit may 
overlap with the screening visit. If these procedures were performed at screening within the time 
window mentioned before (day -14 to day -1 to start of study agent), they do not need to be repeated 
unless otherwise directed by the treating physician.  
At this time patients will answer the clinical rating scales: BAI, BDI, OASIS, EORTC QLQ-C30 
and QLQ-BN20, PSQI, BPI, VAS, PDS, PDI, Side effect symptom questionnaire (SEQ), Treatment 
Expectancy Questionnaire, and a questionnaire designed to assess previous cannabis/cannabinoid 
exposure (if this was not administered in the screening visit).  
 
After completing the study assessments, patients will be randomized to receive study product 
(N=24) or placebo (N=12).  
 
Patients will receive detailed administration instructions along with study drug diaries to document 
product use over the course of the study; they will be instructed how to draw one full dropper of 
study product, deposit the amount in the dropper under the tongue, hold for at least two minutes, 
then swallow.  
 
Only after a subject has been assigned a study ID but prior to any study product administration, 
blood specimens will be collected to perform  (~2 teapoons) to perform endocannabinoid analysis 
and inflammatory biomarkers (see Appendix 3 and section 10.2 for details on specific markers). 
Safety laboratories may be repeated if they are > 3 weeks from day 1 of treatment unless otherwise 
indicated by the investigator. Urine collection does not need to be repeated if a sample was collected 
within 4 weeks of beginning of treatment unless otherwise indicated by the investigator (see Table 
3).   

Protocol Version 2.7 
 
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Protocol date: 01AUG24 
 
5.3    Treatment period  
The treatment period begins at the first day of dosing and for up to 8 weeks (56 days +/-3). Study 
agent should start within day 1 to day 14 of radiation therapy. All patients will self-administer 
1mL of study product (approximately 250mg of CBD) or placebo sublingually two times daily 
(BID) for 8 weeks. 
All patients will complete remote clinical ratings every 2 weeks (14 days +/-3) throughout the study. 
At each timepoint patients will answer the clinical rating scales: BAI, OASIS, BDI, the EORTC-
QLQ-C30 and QLQ-BN20, VAS, PDS, PDI, patient global impression of change scale (PGIC), 
PSQI, SEQ, the Treatment Expectancy Questionnaire, and a questionnaire designed to assess study 
drug compliance. To reduce patient burden, only a subset will be required at each timepoint (e.g. at 
weeks 2 and 6, only the BAI, BDI, VAS, and SEQ will be administered). Refer to Table 3 for details 
on instruments administered at each timepoint. 
 
All participants will complete a brief remote visit (toxicity check) by phone or video visit after 1 
week (7 days +/-3)  of the first dose in order to assess potential adverse events, to ensure compliance 
and to check general mood and quality of life.  
 
The 4 -week (28 days with treatment with study agent, +/-3) visit may take place in person 
(preferred) or remotely according to the clinic’s ability. Additionally, at this timepoint standard of 
care safety laboratories data will be collected (CBC, liver function tests) from safety laboratories 
performed per SOC during chemoradiation.  These tests can be performed at a local laboratory(see 
Table 3) 
 
Subjects will receive sufficient study product (placebo or High-CBD product) from the 
investigational at the beginning of the treatment period and at week 4.  
Adverse events will be monitored continuously throughout the study. Subjects will be encouraged 
to contact the investigator or study team with any questions regarding the study or concerns about 
side effects. Additionally, for subjects who decide to participate in the optional research activity 
using MyStoriTM mobile application, they will be asked to use the application continuously 
throughout the study (see details in section 5.5). 
5.4    End of Study (In-person) 
Participants will return for an end-of-study visit after 8 weeks (56 days +/-3)of treatment with the 
study product. The end-of-study visit will include additional clinical rating scales: 
BAI, BDI, OASIS, EORTC QLQ-C30 and QLQ-BN20, PSQI, BPI, VAS, PDS, PDI, SEQ, the 
PGIC, Treatment Expectancy Questionnaire, and a questionnaire designed to assess medication 
compliance.  
Subjects will undergo a blood draw to assess levels of both circulating endocannabinoids, which 
may be a predictor of treatment response, and exogenous cannabinoids, in order to ensure study 
drug compliance and help confirm that no additional cannabinoid products were used during the 
trial.  

Protocol Version 2.7 
 
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Protocol date: 01AUG24 
A review of their post radiation MRI will take place; this may occur at a separate visit from the final 
study visit depending on SOC treatment plan. The review of the MRI does not require the participant 
to take any actions beyond what is established in their SOC treatment plan.  
Additionally, safety laboratory tests (will be performed  as per Table 3 SOE). Similarly, a blood 
specimen will be obtained to test for endocannabinoid analysis and inflammatory biomarkers (see 
appendix 3 for details)  
5.5 MySTORITM mobile application (Optional) 
Subjects will be offered to opt-in to use the MySTORITM mobile application as an optional research 
activity. The application was developed for brain tumor patients and caregivers by the Neuro-
Oncology Branch (NOB) at the National Cancer Institute (NCI). With the objective of tracking and 
managing symptoms, side effects, organize and manage self-care activities as well as clinical care. 
Subjects who agree to participate in this section will be instructed on how to use the application 
either in-person or in remote sessions. Subjects will be asked to use the side effect, symptom 
logging, and medication intake tracker (at minimum) function of the application. At each visit they 
will be instructed to generate a report using this function in the application and send it to the 
investigators. This report can be sent using secure communication channels: secure e-mail, 
MyChart, or upload directly in to their electronic record on RedCap. 
The objective of using this application is to compare asynchronous symptom and adverse event 
reporting at the time of clinic visit with near real-time reporting.  
This mobile application is intended to be used as symptom tracker and journaling for the patients. 
Given that the mobile application stores data locally in the participant’s device, it does not 
communicate with 3rd parties.  
6 
CRITERIA FOR EVALUATION 
6.1    Primary Endpoint 
• 
The primary endpoint for this study will be the difference between baseline and 8 week 
clinical rating scores on the BAI and OASIS in the CBD+SOC group compared to the SOC 
group. Clinical improvement will be defined as greater than or equal to 15% reduction in 
baseline scores on the BAI. 
6.2    Secondary and Exploratory Endpoints 
• 
The secondary endpoints for this study will be improvement on measures of pain and quality 
of life (BPI, VAS, PDS, PDI, PSQI, EORTC QLQ-C30 and QLQ-BN20, PGIC) after 8 
weeks of treatment with CBD compared to patients in the SOC group. 
• 
Additionally, we will describe tumor progression differences between the CBD+SOC and 
SOC groups by using MRI, including where feasible diffusion tensor imaging (DTI), and 
perfusion imaging. 
6.3    Safety Evaluations 
SOC includes a full laboratory panel concurrent with the screening visit, which will be reviewed 
prior to inclusion in the study – see Table 3 SOE.. If patients present with transaminases >3 times 
UNL at screening, laboratory tests may be repeated. Patients may not be enrolled if transaminases 
are above the stated limit <24 hours prior to day 1 of treatment. Patients will be discontinued if they 
have elevated levels (>3x the normal upper limit) while taking the study drug. Additionally, patients 

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will be tested for kidney function measuring creatinine calculated using the Cockroft and Gault 
formula (>1.5 x ULN). 
 
Suicidality will be assessed using question #9 of the BDI. Investigators and staff must follow the 
suicidality SOP will be followed in the event that suicidal ideation is disclosed (see appendix 1). 
 
All adverse events will be queried and reported at study visits. Further, all adverse events will be 
graded using the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE V5.0) 
and relatedness to the study product will be recorded. 
 
For a subset of patients who opt-in, the MySTORITM app will be used to log-in symptoms, symptom 
impact on physical functions, track self-care activities, track treatments and clinical appointments. 
At each clinic visit, participants will be asked to generate the PDF report and share it with 
researchers.  The MySTORITM app will be used as an additional resource for patients and does not 
replace appointment systems and symptom reporting established by the neuro-oncology clinic.  
 
7 
SUBJECT SELECTION 
7.1    Study Population 
Subjects with newly diagnosed glioblastoma (IDH-wildtype glioblastoma, grade 4) who meet the 
inclusion and exclusion criteria will be eligible for participation in this study.   
7.2    Inclusion Criteria 
1. 
Male or female ≥ 18 years of age 
2. 
Documentation of newly diagnosed glioblastoma, evidenced by neuropathology report and 
based on WHO 2021 classification (IDH-mutant glioblastoma grade 4), and who are to 
undergo SOC (~ 6 weeks of treatment) with radiation and temozolomide (patients using 
Optune may be included) 
3. 
Written informed consent obtained from subject or subject’s legal representative and ability 
for subject to comply with the requirements of the study 
4. 
Fluent in English  
5. 
Scores a minimum of 16 on the Beck Anxiety Inventory (BAI) OR a minimum of 8 on the 
Overall Anxiety Severity and Impairment Scale (OASIS) at the screening visit. Re-testing is 
allowed if it is within the stipulated windows (see section 5.1) 
6. 
Stable medication/psychotherapy regimens for at least 1 month prior to starting the study 
(excluding new glioblastoma treatment-related medications or radiation) 
7. 
KPS of 60 or higher 
7.3    Exclusion Criteria 
1.    Pregnant, breastfeeding, or unwilling to practice birth control during participation in the 
study. 
2. Presence of a condition or abnormality that in the opinion of the Investigators would 
compromise the safety of the patient or the quality of the data. 

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Protocol date: 01AUG24 
3. Current substance use disorder, psychotic disorder, bipolar disorder, or eating disorder 
4. Current use of recreational cannabis, medical cannabis, or hemp-derived cannabinoid products 
more frequently than 1x/month; positive urine THC test 
5. Presence of a serious or unstable medical illness, including liver, kidney, or cardiovascular 
disease. The following laboratories will be performed used to confirm normal function of 
systems within 28 days of day 1 of start study treatment: 
a. Creatinine >1.5 x ULN (Cockroft and Gault) 
b. AST > 3.0 x ULN 
c. ALT > 3.0 ULN 
d. Total bilirubin > 3.0 x ULN 
e. Platelet count outside of normal limits 
f. ANC outside of normal limits 
6. Current use of valproate (due to potential for drug-drug interactions) 
7. Receiving additional, concurrent, active investigational drug for glioblastoma other than 
standard of care. Dietary therapies, like ketogenic etc.do not exclude patients. 
8. Have received any prior treatment for glioma including but not limited to:  
a. Prolifeprospan 20 with carmustine wafer 
b. Prior intracerebral, intratumoral, or cerebral spinal fluid (CSF) agent 
c. Prior radiation treatment for glioblastoma or lower-grade glioma 
d. Prior chemotherapy or immunotherapy for glioblastoma or lower-grade glioma  
9. Contraindication to MRI such as non-MR conditional medical devices or ferrous retained 
foreign bodies. 
10. Additionally, concomitant medications will be assessed on a case-by-case basis with the study 
physician;  
a. participants will be excluded if they are taking strong inhibitors or inducers of 
CYP3A4 (e.g. fluconazole, fluoxetine, fluvoxamine, ticlopidine, St. John’s Wort, 
etc.), CYP2C19 (e.g. ketoconazole, erythromycin, etc.), or CYP2D6 (e.g. 
paroxetine, buproprion, quinidine, ritonavir, glutethimide, etc.).   
b. In addition, participants will be excluded if they are taking blood thinners (e.g. 
warfarin, ticlopidine, rivaroxaban, ticagrelor, apixaban), carbamazepine, 
oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, primidone, clobazam, 
lamotrigine, zonisamide, dexamethasone+, dronabinol, or dulcolax.  
+ It is recognized that patients may require dexamethasone once on clinical trial. If so, they will 
not be excluded at that point. However, the dose needs to be <4mg at the start of the trial 
Dosing schedules may be adjusted in order to offset CB administration with concomitant 
medications to decrease the likelihood of any drug-drug interactions. Subjects must have been on 
stable medication/psychotherapy regimens for at least 1 months prior to starting the study (excluding 
new glioblastoma treatment-related medications or radiation).  
 
 

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8 
CONCURRENT MEDICATIONS 
 
Standard of care for anxiety treatment includes medications, such as antidepressants, buspirone, and 
benzodiazepines, as well as psychotherapy. This study is an investigation of a plant-derived 
compound that has promise in the treatment of anxiety. Subjects will not be asked to change their 
current treatment regimen to participate in this study (i.e. discontinue other medications); this study 
will add an ultra-high CB custom-formulated study product to their current regimen. Patients will 
also not be asked to modify their glioblastoma treatment plan in order to participate.  
Common Medications in Glioblastoma Patients 
*patients on these medications will be excluded (see exclusion criteria 10) 
 
CYP3A4 enzyme-inducing AEDs: 
Carbamazepine* 
Oxcarbazepine* 
Phenytoin* 
Fosphenytoin* 
Phenobarbital* 
Primidone* 
Clobazam* 
  
Non-CPYP3A4 enzyme-inducing AEDs:** 
Valproic acid* 
Lamotrigine* 
Zonisamide* 
  
Other concomitant medications commonly used: 
Dexamethasone 
Dronabinol* 
Dulcolax* 
 
Additional Exclusions* 
Blood thinners (Warfarin*, Ticlopidine*, Rivaroxaban*, Ticagrelor*, Apixaban*) 
Strong inducers or inhibitors of 3A4, 2C19, or 2D6 (https://drug-
interactions.medicine.iu.edu/MainTable.aspx) 
 
8.1    Allowed Medications and Treatments 
Standard therapy for newly diagnosed glioblastoma is allowed except for treatments noted in the 
exclusion criteria described above and as noted in the prohibited medications section below.   
Concomitant medications will be allowed and will be assessed on a case-by-case basis with the 
study physician (see above). 

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9 
STUDY TREATMENTS 
9.1    Method of Assigning Subjects to Treatment Groups 
Up to 36 eligible patients will be randomly assigned to high-CB product or standard of care 
alone groups in a 2:1 ratio. Formulation of Test Product 
We will use the staff and expertise of the Marijuana Investigations for Neuroscientific Discovery 
(MIND) Program at McLean Hospital, directed by co-PI Dr. Staci Gruber, to accomplish 
randomization as they have successfully done this for FDA-approved clinical trials using similar 
study products.  
The ultra-high CBD study product will contain approximately 250 mg/ml of cannabidiol (CBD), 
and will be formulated in medium chain triglyceride (MCT) oil. The solution will also include a 
small amount of THC (approximately 0.6 mg/ml). Participants will self-administer 1 mL of the 
solution BID.  
 
The based used to formulate the high-CBD study product was derived from a proprietary strain of 
industrial hemp grown and processed by Open Book Extracts (OBX). Ethanol extraction was used 
to create a distillate, which allows for the retention of some terpenes and flavonoids. The final 
solution was made by diluting the extract by a factor of approximately 4, and mixing with MCT oil. 
 
# 
bottles 
Bottle 
Size 
Total 
Solution 
Total 
CBD 
Extract 
required1 
Emulsifier 
required 
MCT Oil 
required2 
50 
30 mL 
1500 mL 
379 g 
392.89 g 
0 g 
1032 g 
(250 mg/mL) 
(27.6%) 
(0.0%) 
(72.4%) 
1) Based on a raw extract with ~ 96.4% CBD by weight 
2) Based on an MCT oil density of ~ 0.95g/mL 
 
9.2    Packaging and Labeling 
 
Packaging: The study product will be bottled into 30-mL glass bottles with calibrated droppers.  A 
tamper-evident heat-shrink band will be used to secure the cap.   
 
Labeling: The bottles will be labeled with the batch ID, contact information for the PI, directions 
for use, and the statement “Caution: New Drug – Limited by Federal law to investigational use.” 
See below for mock-up of label: 
 

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Protocol ID:  
PIs: Dr. Butowski, Dr. Gruber 
Phone: (415) 353-2966, (617) 855-2762 
Directions for use: Deposit 1 dropper under 
the tongue, hold for approximately 2 
minutes, then swallow. Take two times daily: 
once in AM, and once in PM.  
 
Caution: New Drug – Limited by Federal law 
to investigational use 
 
Placebo study products will be packaged and labeled in an identical manner to the active study 
product. 
9.3   Supply of Study Drug at the Site 
Study Drug will be shipped or delivered by local courier to the investigational sites.  The initial 
study drug shipment will be delivered after approval. Subsequent study drug shipments, if 
necessary, will be made after request for resupply and it is subject to product availability. 
9.3.1    Dosage/Dosage Regimen 
Patients will self-administer 1 ml (approximately 250mg/ml for the CBD group) of study product 
sublingually two times daily (BID). 
1.3.2 
Dispensing 
UCSF Investigational Drug Services (IDS) will manage drug accountability records for UCSF 
study supply of investigational product(s). 
9.3.3    Administration Instructions 
Patients will receive detailed administration instructions along with study drug diaries to document 
product use over the course of the study; they will be instructed how to draw one full dropper of 
compound, deposit the amount in the dropper under the tongue, hold for at least 2 minutes, then 
swallow. 
9.3.4    Storage 
Study drug should be stored by the study site at controlled room temperature, 15 to 30ºC (59 to 
86ºF). If the temperature of study drug storage in the clinic/pharmacy exceeds or falls below this 
range, this should be reported to the Sponsor or designee and captured as a deviation. Subjects will 
be instructed to store the medication in original packaging at room temperature according to the 
instructions outlined on the Drug Administration Instructions. 
As this product was created from industrial hemp, per the Agricultural Improvement Act of 2018 it 
is not scheduled under the Controlled Substances Act.  
9.4    Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each subject will 
be maintained on an ongoing basis by a member of the study site staff.  The number of study drug 

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dispensed and returned by the subject will be recorded on the Investigational Drug Accountability 
Record.  The principal investigators and/or their designee will verify these documents throughout 
the course of the study. 
9.5    Measures of Treatment Compliance 
Subjects will be asked to keep a patient diary noting the day and date they take their study drug and 
any adverse event. They will be asked to bring their patient diary to each study visit along with all 
used and unused study drug containers. 
For the subset of participants who opt-in to the use of MySTORITM app, they will be asked to log 
their study medication intake in the mobile application. 
10 STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the duration 
of the study is diagrammed in Table 3. 
Prior to conducting any study-related activities, written informed consent and the Health Insurance 
Portability and Accountability Act (HIPAA) authorization must be signed and dated by the subject 
or subject’s legal representative.  
10.1    Clinical Assessments 
10.1.1    Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at Baseline and each study 
visit at weeks 1,2,4,6,8 and at early termination when applicable. Dose, route, unit frequency of 
administration, and indication for administration and dates of medication will be captured. 
10.1.2    Demographics  
Demographic information (date of birth, gender, race/ethnicity) will be recorded at Screening. 
10.1.3    Medical History  
Relevant medical history, including history of current disease, and information regarding underlying 
diseases will be recorded at Screening 
10.1.4    Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. Duration 
(start and stop dates), severity/grade, outcome, treatment and relation to study drug will be recorded 
on the case report form (CRF). 
10.2    Clinical Laboratory Measurements  
10.2.1    Pregnancy Test 
A urine or serum pregnancy test will be obtained from female subjects who are of childbearing age 
prior to their participation in the study. 
10.2.2    Urinalysis 
Urine will be obtained at screening only for determination of THC 

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10.2.3    Cannabinoid and endocannabinoid analysis 
A blood sample of ~3mL will be collected on a properly labeled K2 EDTA 5.4mg at baseline, prior 
to start study treatment and at the end of study visit to test for the 12-plex panel that includes: IL-1 
beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-19, IL-12, IL-13, IL-17, IFN-g, TNF-a.  
Samples will be processed according to the guidelines stated on Appendix 3.  
 
The samples will be processed for analysis at the Center for Medicinal Cannabis Research (CMCR): 
University of California, San Diego 
ATTENTION: CMCR Lab 
220 Dickinson Street, Suit B 
Mail Code8231 
San Diego, CA 92103-8231 
 
Whole blood Will be aliquoted into cryovials, barcoded into the labs biorepository system, and 
stored at -80oC until analysis. 
 
Note: standard laboratory tests for patients under temozolomide treatment will be performed at 
customary timepoints as per standard of care practice and at the discretion on the treating physician 
and data will be recorded.  
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1    Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient 
administered a pharmaceutical product and that does not necessarily have a causal relationship with 
the treatment.  An AE is therefore any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the administration of an 
investigational product, whether or not related to that investigational product.  An unexpected AE 
is one of a type not identified in nature, severity, or frequency in the current Investigator’s Brochure 
or of greater severity or frequency than expected based on the information in the Investigator’s 
Brochure. 
The Investigators will probe, via discussion with the subject, for the occurrence of AEs during each 
subject visit and record the information in the site’s source documents.  Adverse events will be 
recorded in the patient CRF.  Adverse events will be described by duration (start and stop dates and 
times), severity, outcome, treatment and relation to study drug, or if unrelated, the cause. 
Additionally, a subset of subjects who agree to participate will be identified to enroll in the 
MySTORITM mobile application to track and log symptoms and adverse events. At each visit, 
participants will share the report generated by the app with the investigators and will be included in 
the study record. This tool will not replace the investigator’s discussion with the subject for 
occurrence of AE during each visit. 
11.2    AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0 should be used to assess and grade AE severity, including laboratory abnormalities 
judged to be clinically significant. The modified criteria can be found in the study manual.  If the 
experience is not covered in the modified criteria, the guidelines shown in Table 1 below should be 

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used to grade severity.  It should be pointed out that the term “severe” is a measure of intensity and 
that a severe AE is not necessarily serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically might 
have caused death if it were more severe. 
 
11.3    AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the guidelines 
in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the drug; 
that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the drug; 
that follows a known or expected response pattern to that suspected drug; but that 
could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
 
11.4    Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 
• 
death 

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• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on appropriate medical 
judgment, they jeopardize the subject or require intervention to prevent one of the outcomes listed.  
 
11.4.1    Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) per UCSF IRB 
Guidelines.  The collection period for all SAEs will begin after informed consent is obtained and 
end after procedures for the final study visit have been completed. 
 
In accordance with the standard operating procedures and policies of the local Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC), the site investigators will report SAEs to the 
IRB/IEC.   
 
All serious adverse events are entered into OnCore, as well as submitted to the IRB. The SAEs are 
reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and 
discussed at DSMC meetings, which take place every eight weeks.  The date the SAE was sent to 
all required reporting agencies will be documented in OnCore.  
 
If a death occurs during the study and is determined to be possibly, probably, or definitely related 
either to the study procedure, the Investigator or his/her designee must notify the DSMC Chair or 
Vice Chair and DSMC Director within one business day.     
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1   Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject, the investigators, or 
the Sponsor feels that it is not in the subject’s best interest to continue.  The following is a list of 
possible reasons for study treatment discontinuation 
• 
Subject withdrawal of consent (or assent) 
• 
Subject is not compliant with study procedures 
• 
Adverse event that in the opinion of the investigator would be in the best interest of the 
subject to discontinue study treatment 
• 
Protocol violation requiring discontinuation of study treatment 
• 
Lost to follow-up 
• 
Sponsor request for early termination of study 
• 
Positive pregnancy test (females) 
 
Study Termination Criteria 

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Patients may withdraw at any time and for any reason, and the PIs may discontinue a patient based 
on their clinical judgment. In addition, a patient’s participation in the trial will end if any of the 
following criteria are met: 
a) Completion of the study 
b) Patient reports adverse effects of study product and wishes to leave the study, or if study 
staff determine that study termination is appropriate based on the development of significant 
anxiety or paranoia, reports of undesired intoxication, reports of significant changes in heart 
rate (ie. palpitations, tachycardia) or blood pressure, initiation of contraindicated 
concomitant medication, or any suicidal ideation; while occurrence of these events is very 
unlikely, they will be monitored at each visit and the SOP included in appendix 1 will be 
followed. 
c) Patients taking anticonvulsants with elevated transaminases >3x the normal upper limit will 
be discontinued if they exhibit elevated levels while taking the study drug 
d) Patient does not use solution as directed; if a patient endorses taking more study product 
than directed, the study team will first go through the standard dosing instructions with them 
again and re-iterate the amount to be taken and how often. If, at the next visit, the patient is 
still taking significantly more than directed (i.e. >50% increase in daily total dose), they 
will be terminated from the study 
e) Any study exclusions are met (i.e. change in medical status, pregnancy, other cannabinoid 
use, etc.) 
f) Inpatient hospitalization >48hrs or hospice care is initiated 
 
If a subject is withdrawn from treatment due to an adverse event, the subject will be followed and 
treated by the Investigators until the abnormal parameter or symptom has resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation visit as 
soon as possible and then should be encouraged to complete all remaining scheduled visits and 
procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigators to provide a reason for subject withdrawals.  
The reason for the subject’s withdrawal from the study will be specified in the subject’s source 
documents Refer to Section 10 for early termination procedures. 
12.2    Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigators, or the 
Sponsor feels that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigators to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in the 
subject’s source documents.  As noted above, subjects who discontinue study treatment early (i.e., 
they withdraw prior to Visit 7) should have an early discontinuation visit. Refer to Section 10 for 
early termination procedures.   
12.3    Replacement of Subjects 
Subjects who withdraw from the study (both arms) will be replaced.    

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Protocol date: 01AUG24 
Subjects who are withdrawn from the study by the investigator will be replaced.   
 
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, investigators fail to adhere to significant protocol 
requirements affecting the inclusion, exclusion, subject safety and primary endpoint criteria.  
Protocol violations for this study include, but are not limited to, the following: 
-Enrollment of a subject who failed to meet inclusion/exclusion criteria 
-Use of a prohibited concomitant medication without the Principal investigator’s approval 
-Major deviations from the protocol that pose a safety risk for the subject 
When a protocol violation or incident occurs, it will be discussed with the investigators and a 
Protocol Violation Form detailing the violation will be generated.  The HDFCCC DSMC will review 
the report to ensure that there is a sufficient root cause analysis and a corrective and preventive 
action plan in place to address the violation or incident. This form will be signed by the Investigator. 
A copy of the form will be filed in the site’s regulatory binder.  
14 DATA AND SAFETY MONITORING  
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) DSMC will be the 
monitoring entity for this trial (see DSMC Monitoring Plan in Appendix 2).  
15 STATISTICAL METHODS AND CONSIDERATIONS 
15.1    Descriptive Statistics 
Descriptive statistics will be summarized for all randomized subjects. For continuous variables will 
include the number of subjects (n), mean, median, standard deviation, minimum and maximum. For 
categorical variables, summaries will include counts of subjects and percentages. Percentages will 
be rounded to one decimal place.  
 
15.2    Analysis of Primary Endpoints 
The primary endpoint of the trial will be change in anxiety scores measured by the BAI and 
OASIS instruments. Instruments will be administered to eligible subjects as per the schedule of 
events (Table 3). Analysis will be conducted in a hierarchy, first testing the change in scores based 
only on randomization, then stratified by MGMT methylation status and finally stratified by IDH 
status. This will be evaluated by applying a mixed effects multivariate regression model with all 
relevant variables that include but not limited to: age, sex, race/ethnicity and extent of resection.  
 
Clinical response (defined as >15% reduction in BAI scores from baseline) will be evaluated after 
the 9th subject has completed their 8 week trial. If >15% reduction in average BAI scores has not 
been achieved, the dosing will increase to three times per day (TID) for a total daily dose of 750mg 
CBD in the CBD+SOC group. 
 

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15.3    Analysis of Secondary Endpoints 
Secondary endpoint, change in quality of life score measured by the EORTC-QOL will be 
assessed in the randomized population at baseline, and over the treatment course of the trial. Similar 
to the primary endpoint, a mixed effects multivariate regression model containing all relevant 
variables will be used for analysis.  
Disease state and response to therapy will be determined using Response Assessment in Neuro-
Oncology (RANO) criteria (DOI: 10.1200/JCO.2009.26.3541) based on structural MRI. We will 
observe PFS at 6 and 12m and OS over 24m.  
 
Additionally, advanced MRI including DTI and perfusion imaging will be obtained at scheduled 
standard of care MRI timepoints. Qualitative diffusion and perfusion characteristics will be used to 
support the evaluation of changes in structural MRI that may represent tumor growth (progressive 
disease) or post-treatment changes (“pseudoprogression”) commonly seen in glioblastoma in the 
period immediately following chemoradiotherapy. Further, quantitative measures of diffusion 
(mean diffusivity, MD; fractional anisotropy, FA) and perfusion (relative cerebral blood volume, 
rCBV) will be used to assess changes between control and treatment groups. 
 
Response assessment as well as DTI and perfusion processing and analysis will be performed by 
the study neuroradiologist, Javier Villanueva-Meyer, and his laboratory. 
15.4    Analysis of Exploratory Endpoint 
Disease state and response to therapy will be determined using Response Assessment in Neuro-
Oncology (RANO) criteria (Wen et al., 2010) based on structural MRI and interpreted by Dr. 
Butowski with any necessary assistance provided by UCSF Neuroradiology.  
 
Additionally, advanced MR techniques including DTI and perfusion imaging will be obtained at 
scheduled SOC MRI timepoints. Qualitative diffusion and perfusion characteristics will be used to 
support the evaluation of changes in structural MRI that may represent tumor growth (progressive 
disease) or post-treatment changes (“pseudoprogression”) commonly seen in GBM in the period 
immediately following chemoradiotherapy. Further, quantitative measures of diffusion (mean 
diffusivity [MD], fractional anisotropy [FA]) and perfusion (relative cerebral blood volume [rCBV]) 
will be used to assess changes between the CBD+SOC and SOC groups.  
 
15.5    Sample Size and Randomization 
We plan to enroll (i.e. assigned a treatment by randomization) 36 subjects: 24 subjects will be 
assigned to receive high-CBD along with SOC for chemoradiation (CBD+SOC) and 12 to receive 
SOC plus placebo.  
Power analyses indicate that for 2x6 mixed model analyses (2 groups with 6 time points each) to 
detect medium effect sizes (Cohen’s f=.35) at power 80% and alpha level 0.05, a minimum of 12 
individuals per group is required assuming a correlation coefficient of the outcome over time of 0.5. 
Given the pilot nature of this investigation, a larger sample size in the active treatment group confers 
additional statistical power for monitoring safety and efficacy, and is justified given the likelihood 
of clinical benefit.  
 
Randomization will take place on a 2:1 fashion (CBD+SOC: SOC plus placebo) following the 
procedure below (figure 2): 

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Protocol date: 01AUG24 
15.6    Data Sets Analyzed 
All eligible patients who are randomized into the study and receive at least one dose (the Safety 
Population) will be included in the safety analysis. 
 
16 DATA COLLECTION, RETENTION AND MONITORING 
16.1    Data Collection Instruments 
The Investigators will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each subject treated with the study drug.   
Data from participants will be stored in REDCap a secure web-based database. Subjects will be 
assigned a sequential number following randomization to identify them in the database. Only the 
research team will have access to such data.  
In the event that a survey is e-mailed to the participants the data will be de-identified and the PI, co-
PI and/or their designee(s) will have a key to be able to identify the data in case an authority requires 
so 
and 
for 
data 
analysis. 
Given 
the sensitivity of the information collected on the questionnaires, the patient will be advised that the 
information shared will be strictly for research and will remain de identified and confidential.  
Study personnel will enter data from source documents corresponding to a subject’s visit into the 
protocol-specific electronic Case Report Form (eCRF) when the information corresponding to that 
visit is available. Subjects will not be identified by name in the study database or on any study 
documents to be collected by the Sponsor (or designee), but will be identified by a subject number 
and initials. 
The Investigators are responsible for all information collected on subjects enrolled in this study.  All 
data collected during the course of this study must be reviewed and verified for completeness and 
accuracy by the Investigator.  A copy of the CRF will remain at the Investigators’ site at the 
completion of the study. 
16.2    Data Management Procedures 
The data will be entered into a validated database.  The Data Management group will be responsible 
for data processing, in accordance with procedural documentation.  Database lock will occur once 
quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials. 
16.3    Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. The study database will 
be updated in accordance with the resolved queries.  All changes to the study database will be 
documented. 
16.4    Archival of Data 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate 
backup 
copies 
of 
the 
database 
and 
related 
software 
files 
will 
be 
maintained.  Databases are backed up by the database administrator in conjunction with any updates 
or changes to the database.   

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At critical junctures of the protocol (e.g., production of interim reports and final reports), data for 
analysis is locked and cleaned per established procedures. 
16.5    Availability and Retention of Investigational Records 
The Investigators must make study data accessible to the monitor, other authorized representatives 
of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) inspectors upon request.  
A file for each subject must be maintained that includes the signed Informed Consent, HIPAA 
Authorization and Assent Form and copies of all source documentation related to that subject.  The 
Investigators must ensure the reliability and availability of source documents from which the 
information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study File 
Notebook, etc.) must be kept secured for a period of two years following marketing of the 
investigational product or for two years after centers have been notified that the IND has been 
discontinued.  There may be other circumstances for which the Sponsor is required to maintain study 
records and, therefore, the Sponsor should be contacted prior to removing study records for any 
reason. 
16.6    Monitoring 
Monitoring visits will be conducted by representatives of the UCSF Hellen Diller Cancer (HDCC) 
Center according to the U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).    
By signing this protocol, the Investigators grant permission to the UCSF HDCC (or designee), and 
appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all appropriate 
study documentation. 
16.7    Subject Confidentiality 
In order to maintain subject confidentiality, only subject number and subject initials will identify all 
study subjects on CRFs and other documentation submitted to the Sponsor.   
 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records 
will be identified by a coded number and initials only.  All study records will be kept in a locked 
file cabinet and code sheets linking a patient’s name to a patient identification number will be stored 
separately in another locked file cabinet.  Clinical information will not be released without written 
permission of the subject, except as necessary for monitoring by the FDA.  The Investigators must 
also comply with all applicable privacy regulations (e.g., Health Insurance Portability and 
Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
17.1    Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each participating 
center prior to study initiation.  Serious adverse experiences regardless of causality will be reported 
to the IRB/IEC in accordance with the standard operating procedures and policies of the IRB/IEC, 
and the Investigators will keep the IRB/IEC informed as to the progress of the study.  The 
Investigators will obtain assurance of IRB/IEC compliance with regulations. 

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Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning patient recruitment, 
payment or compensation procedures, or other pertinent information) will be submitted to the 
IRB/IEC.  The IRB/IECs written unconditional approval of the study protocol and the informed 
consent form will be in the possession of the Investigators before the study is initiated.  The 
IRB/IECs unconditional approval statement will be transmitted by the Investigators to the Sponsor 
or designee prior to the shipment of study supplies to the site.  This approval must refer to the study 
by exact protocol title and number and should identify the documents reviewed and the date of 
review. 
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB/IEC approval except when necessary to eliminate immediate hazards to the patients or 
when the change(s) involves only logistical or administrative aspects of the study.  Such 
modifications will be submitted to the IRB/IEC and written verification that the modification was 
submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect adversely 
the safety of the patients of the conduct of the study; an annual update and/or request for re-approval; 
and when the study has been completed. 
17.2    Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US 
Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, and 
CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if 
applicable), and local regulations. 
The Investigators will prepare the informed consent form, assent and HIPAA authorization and 
provide the documents to the Sponsor or designee for approval prior to submission to the IRB/IEC.  
The consent form generated by the Investigators must be acceptable to the Sponsor and be approved 
by the IRB/IEC.  The written consent document will embody the elements of informed consent as 
described in the International Conference on Harmonisation and will also comply with local 
regulations. The Investigators will send an IRB/IEC-approved copy of the Informed Consent Form 
to the Sponsor (or designee) for the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to entering 
the subject into the trial.  Information should be given in both oral and written form and subjects (or 
their legal representatives) must be given ample opportunity to inquire about details of the study.  If 
appropriate and required by the local IRB/IEC, assent from the subject will also be obtained.  If a 
subject is unable to sign the informed consent form (ICF) and the HIPAA authorization, a legal 
representative may sign for the subject.   A copy of the signed consent form (and assent) will be 
given to the subject or legal representative of the subject and the original will be maintained with 
the subject’s records. 
17.3    Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigators agree to: 
1. 
Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when to protect the safety, rights or welfare of subjects. 
2. 
Personally conduct or supervise the study (or investigation). 

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3. 
Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. 
Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. 
Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments. 
6. 
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make 
those records available for inspection with the Sponsor (or designee). 
7. 
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. 
Promptly report to the IRB and the Sponsor (or designee) all changes in the research activity 
and all unanticipated problems involving risks to subjects or others (to include amendments 
and IND safety reports). 
9. 
Seek IRB approval before any changes are made in the research study, except when necessary 
to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 
 

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TABLE 3.   SCHEDULE OF ASSESSMENTS 
Study visit 
Screeningq 
Baseliner 
Treatment period 
End of 
Treatment 
Follow up 
Day -28 to -1 
of study 
agent   
 
Up to 14 
days of 
start of RT 
Treatment 
Week 1a 
Treatment 
Week 2  
Treatment 
Week 4b 
Treatment 
Week 6 
Treatment 
Week 8 
 
Day 
 
 
7 
(+ 3  days) 
 14 
(+3days) 
28 
(+ 3 days) 
42 
(+ 3 days) 
56(+ 14  days)s 
Month 3, 
6, 12, 24 
post-
baseline(
+/- 14 
days)t 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History 
Xp 
 
 
 
 
 
 
 
Complete Physical Exam 
X 
 
 
 
 
 
Xo,p 
 
Karnofsky Performance 
Status 
X 
X 
 
 
 
 
 
 
Abbreviated Physical 
Exam 
 
Xn 
 
 
X  
(optional) 
 
Xo,p 
 
Height  
X 
 
 
 
 
 
 
 
Weight  
X 
X 
 
 
 
 
 
 
Vital Signs  
X 
X 
 
 
 
 
 
 
Urine samplej 
X 
 
 
 
 
 
 
 
Standard lab testsk (data 
collection) 
X  
 
X 
 
 
X 
 
X 
 
Research biomarkersl 
 
Xl 
 
 
 
 
Xk,l 
 
Pregnancy Test (Urine Or 
Serum)c 
X 
Xc 
Xc 
 
Randomization 
X 
 
 
 
 
 
 
 

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Drug Dispensation  
 
X 
 
 
X 
 
 
 
Drug Administration 
 
X 
Xs 
 
Subject Diary Review 
and Drug Accountability m 
 
 
X 
X 
X 
X 
X 
 
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
Evaluationm 
X 
 
X 
X 
X 
X 
X 
 
Self-administered 
questionnaires d 
Xf,i 
Xf,i 
Xe,g 
Xh 
Xe,g 
Xh 
Xe,g 
 
Survival Follow up (Via 
Chart review) 
 
 
 
 
 
 
 
X 
 
a.  First dose should occur  between day 1 and 14 of radiation therapy. 
b. Week 4 visit may be completed in person if the patient or investigators choose to do so. While remote visit is allowed , in-person visit is preferred if feasible. 
c. For Women of Child Bearing Potential only. It is mandatory at study entry. Test may be repeated if treating physician deems it appropriate. 
d. The instruments: Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), Overall Anxiety Severity and Impairment Scale (OASIS), the European Organisation for 
Research and Treatment of Cancer(EORTC) QLQ-C30 and brain module (BN20), the Pittsburgh Sleep Quality Index (PSQI), the Brief Pain Inventory(BPI), a Pain Visual Analog 
Scale (VAS), the Pain Distress Scale (PDS), the Pain Disability Index (PDI), the Tx Expectancy questionnaire, Patient’s Global Impression of Change scale (PGIC), and a 
questionnaire designed to assess previous cannabinoid exposure. Instruments will be completed on a self-administered fashion. Patients will be provided with a link to complete 
measurements online. If patients are unable to answer online, they will be provided with paper versions.   
e. Patients will be administered with Side Effects Questionnaire (SEQ) and a questionnaire designed to assess dosing compliance. 
f. BAI, BDI, OASIS , QLQ-C30, QLQ-BN20, PSQI, BPI, VAS, PDS, PDI, Treatment Expectancy questionnaire  
g. BAI, BDI, OASIS, QLQ-C30, QLQ-BN20, PSQI, BPI, VAS, PDS, PDI, Treatment Expectancy questionnaire, PGIC 
h. BAI, BDI, VAS, SEQ 
i. Questionnaire to assess previous cannabis/cannabinoid exposure.  
j. Screening for  THC  in urine. 
k. CBC, liver function tests and chemistry tests will be completed at customary standard of care timepoints and or at the discretion of the treating provider as needed with data 
recorded at screening or baseline (before taking study product(s)), approximately week 4 and week 8 with windows as stated in table. If screening labs within 14 days of baseline 
they do not neeed to be repeated 

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l. Patients will submit blood samples for endocannabinoid analysis and inflammatory biomarkers (Plex-12 panel) at the beginning of treatment but prior to dosing on day 0 and at 
the final visit (see section 8.2.3). Research blood will  be processed  following the guidelines on Appendix 3. 
m. As an optional item subjects will be asked to enter symptoms and side effects using the MySTORITMApp on their personal mobile devices. For those subjects who opt-in to use 
the mobile application, they will be asked to generate the PDF reports and hand them to the investigator at the time of visit. 
n.  Abbreviated exam may be performed at baseline (but after screening) if the investigator deems it appropriate. 
o. End of treatment imaging and safety laboratories will be performed as per customary standard of care practice or at the discretion of the treating provider. The resulting data will 
be recorded accordingly. Abbreviated physical exam may be used in place of complete physical exam if the investigator deems it appropriate 
p. A post-surgical MRI scan will be reviewed as per delineated in section 5.1 (if/when available). This is not a requirement for study enrollment. Similarly, a post-radiation MRI 
scan will be reviewed on or after end of treatment.  
q. If screening procedures are performed when starting radiation therapy (Day 0 +2weeks) the tests can be used as baseline and may be omitted unless otherwise noted by the 
investigator.  
r. This visit may overlap with the screening visit. If the procedures on this visit were performed at screening within the time window, they may be omitted unless otherwise 
directed by the investigator. 
s. Drug administration marks the start of treatment and it will be continuous through day 56. Surveys will be answered at the 56 day (week 8) timepoint (+ 3 days)t. Follow up 
period visits will be completed via chart review 

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I. APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 1. Suicidality policy for subjects with suicidal Ideation 
 
All assessments will be performed electronically or by interview at the clinic. If subjects endorses 
suicidal ideation or screens positive for suicidal ideation (as per the guidelines below) at an in-
person visit the guidelines below should be followed.  
If the subject is found positive for suicidal ideation during an electronic, self-administered screener, 
it will trigger urgent communications (e-mail and notifications) to the Investigators and designated 
staff. Upon receipt of such communication the Investigator or designee will contact the subject via 
phone to further evaluate using the Suicidality Assessment and the protocol will continue as 
delineated below.  
The protocol for situations in which subjects report suicidal ideation at screening, during a visit, or 
on the BDI is as follows:  
Screen/Spontaneous Expression of Suicidality During Visit  
• 
If the subject endorses recent or current thoughts about death, assess current risk 
level following steps outlined in safety planning guidelines, below.  
BDI  
• 
If the subject endorses a “0” for suicidal thoughts or wishes (BDI item 9) no further 
action is required.  
• 
If the subject endorses a “1” for this item, offer information about community 
resources for psychological treatment saying, “I noticed on your questionnaire you 
circled items showing you are feeling distressed.” (See Community Resources folder 
for materials.)  
• 
If a subject endorses a “2” or “3” for this item, assess for current suicidal ideation. 
(See  
SUICIDALITY ASSESSMENT; Determine current level of risk and follow safety planning 
guidelines. (See RISK ASSESSMENT AND SAFETY PLANNING ) 
GUIDELINES (jump to the Risk Assessment section.)  
  
 
 
 

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SUICIDALITY ASSESSMENT 
What types of thoughts are you having about death? (Describe suicidal ideation)  
Do you have a specific plan? Note:  
• 
Time 
• 
Place  
• 
Method (specific & detailed or vague?)  
• 
Access to ___(method)___?  
• 
Knowledge of how to implement?  
• 
expressed intent to carry out the plan?  
 Have you ever felt this way before? (Describe any prior attempts, when these occurred, method 
used, how they survived (did someone find them?), how lethal was the method)  
What has helped you keep yourself safe in the past? (Reasons elicited for living -support)  
Are you currently in treatment with a therapist, psychologist, social worker, or psychiatrist?   
Have you discussed these thoughts/plans with that person? When was your last appointment with 
this person? When is your next appointment? Can you request an earlier appointment?  
(In addition to, or if no therapist) Who can you talk to when you are feeling this way?  
Do you have friends or family that you could call or see now? (Check social support situation - 
likelihood of someone else being around to detect or intervene - and living situation – do they live 
alone, with roommate(s), spouse, parents, etc. Are people close to them aware of how they are 
feeling?)  
Do you have any plans/appointments for this week? (Check to see how future-oriented they are. 
Do they have plans and obligations that they are planning on following through with?)  
On a scale of 0-10 (0 = negative/depressed, 10 = positive) how would you rate your current 
mood?  
On a scale of 0-10, what is your current intent to kill yourself? (Assess level of risk: i.e. low, 
moderate, high, imminent). (FOLLOW STEPS APPROPRIATE TO RISK LEVEL – SEE 
BELOW)  
I’m concerned about you and want you to be safe. Can you promise me that you will page your 
therapist/psychiatrist or go to an ER or call a suicide hotline if you don’t think you can keep 
yourself safe? (Ability to contract for safety)  
What hospital will you go to? How will you get there? (Get specific details, make sure the person 
has a taxi # or their friend’s/family member’s phone number right in front of them)  

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After completing the “SUICIDALITY ASSESSMENT”, go to “RISK ASSESSMENT AND 
SAFETY PLANNING GUIDELINES”   
 
RISK ASSESSMENT AND SAFETY PLANNING GUIDELINES 
 Refer to questions in the Suicidality Assessment section of this document to elicit information 
about the subject’s thoughts of suicide. To determine if current suicidal intent is present ask: 
“On a scale of 0-10, what is your current intent to kill yourself?”  
 Assess level of risk as follows:  
LOW RISK = No past attempt or current intent  
• 
Validate subject’s feelings; offer community resources  
MODERATE RISK = past attempt, but current suicidal intent ≤ 6  
• 
Subject to articulate own safety plan (i.e. what to do if thoughts/urges increase)  
• 
Provide subject with emergency contact numbers: 
o 
911,  
o 
find # of their own clinician,  
o 
National suicide prevention lifeline:1-800-273-TALK (8255)  
o 
San Francisco Suicide Prevention’s hotlines: 415-781-0500 
• 
Call Physician on call at the Neuro Oncology clinic: 415-353-2966 or Nursing line: 
415-353-2652 to inform them of level of risk and to enlist their assistance in getting 
subject to a clinician 
• 
Send MyChart message to physician 
• 
Document safety plan and steps taken to decrease risk  
 HIGH RISK = Current suicidal intent 7-8, but no plan or access to lethal means.  
• 
Subject to articulate own safety plan (i.e. what to do if thoughts/urges increase)  
• 
Encourage subject to immediately contact support(s) and clinician(s) to inform of 
risk.  
• 
Provide subject with emergency contact numbers: 
o 
911,  
o 
find # of their own clinician,  
o 
National suicide prevention lifeline:1-800-273-TALK (8255)  
o 
San Francisco Suicide Prevention’s hotlines: 415-781-0500 
• 
Call Physician on call at the Neuro Oncology clinic: 415-353-2966 or Nursing line: 
415-353-2652 to inform them of level of risk and to enlist their assistance in 
getting subject to a clinician 
• 
Document safety plan and steps taken to decrease risk  
IMMINENT RISK = Current suicidal intent > 6 and specific plan/access; OR current suicidal 
intent 9-10, regardless.  

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• 
Call Physician on call at the Neuro Oncology clinic: 415-353-2966 or Nursing line: 
415-353-2652 to inform them of level of risk and to enlist their assistance in getting 
subject to a clinician  
If in clinic:  
• 
Subject should not be left alone while supports are being contacted.  
• 
If subject refuses to enlist his/her support network, call the physician and inform 
them of subject’s location and risk level.  
• 
Subject can leave the clinic with family member or friend -- someone able to 
accompany them to their own clinician; or someone from the staff team can accompany 
them to ER (located on Parnassus avenue 505 Parnassus Avenue) for an emergency 
evaluation.  
If on the phone:  
 
• 
Subject should not remain at home alone.  
• 
Staff member keeps the subject on the phone while contacting (or enlisting the help 
of colleagues to contact) clinician/people in support network to inform them of level of 
risk and enlist their assistance in getting subject to a clinician or psychiatric emergency 
room.  
• 
If subject refuses to do this: Call 911 and inform of subject’s location and risk 
level.  
• 
Document safety plan and steps taken to decrease risk  
Suicide Risk Factors  
• 
Male gender (females more attempts, males more completions)  
• 
Ethnicity (white attempt and complete more than others)  
• 
Age ≥16 years?  
• 
If male, > 65 years?  
• 
Current psychiatric disorder?  
• 
Current mood disorder (MDD, Bipolar)  
• 
Current substance use disorder (Is the person under the influence of alcohol 
or drugs at this moment?)  
• 
Current psychotic disorder  
• 
Current personality disorder (esp. Borderline PD or Anti-Social PD)  
• 
Other risk factors  
• 
Recent loss, separation/divorce/break-up? Other current stressors?  
• 
Impulsiveness?  
• 
Hopelessness about the future?  
• 
Current distress, irritability, agitation or other “abnormal” mental state  
• 
Depressed mood (On scale 0-10 [0 = neg, 10 = pos] how would you rate 
your current mood?)  
• 
Suicide history and present ideation/planning  
• 
Previous suicide attempt?  
• 
Family history of suicide/attempts/completions?  

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• 
Current plan (SSI item 12)?  
• 
Access to lethal means (firearm, drugs, etc.; SSI #13)?  
• 
Current intent (SSI #14 -15; also, “on a scale of 0-10, what is your current 
intent to kill yourself?)  
• 
Current suicidal ideation? (BDI score of 3 on item 9 and/or a 5 is endorsed 
on the MASQ suicide item)  
Protective Factors:  
• 
In treatment? If so, is clinician aware of risk?   
• 
Family/roommates/friends aware of risk?  
• 
Means restriction (firearms, drugs, family/social support/monitoring)?  
• 
Presence of children in the home, spouse/partner, or other positive relationships?  
 CRISIS NUMBERS (Also refer to Community Resources folder for a more resources):  
• 
911 
• 
National Hopeline Network 1-800-SUICIDE (1-800-784-2433) 
• 
National suicide prevention lifeline:1-800-273-TALK (8255)  
• 
San Francisco Suicide Prevention’s hotlines: 415-781-0500 
• 
Suicide Prevention in Spanish: 1-800-SUICIDA (784-2432) 
• 
UCSF Parnassus Emergency Department: 415-353-1037 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 2. Data and Safety Monitoring Plan for a Phase II or III 
Institutional Trial 
 
A.2.1    Oversight and Monitoring Plan 
 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety 
for all HDFCCC institutional clinical trials.  A summary of DSMC activities for this trial 
includes:  
 
• 
Annual auditing (depending on trial accrual) 
• 
Review of serious adverse events 
• 
Minimum of biennial regulatory auditing 
 
A.2.2 Monitoring and Reporting Guidelines 
 
Investigators will conduct a continuous review of data and participant safety at monthly site 
committee meetings where the results of each participant’s treatment are discussed and 
documented in the site committee minutes.   
 
All institutional Phase II and III therapeutic trials are audited on an annual basis, with all data 
from 20% percent of the enrolled participants audited by the DSMC Monitor/Auditor.   
 
The assigned DSMC Monitor/Auditor will review no more than a total of 10 participant charts 
during the course of auditing this trial. DSMC Monitor/Auditors will send a follow-up report to 
the study team within 20 business days after the auditing visit is complete for the PI and the study 
team to resolve all action items from this report within 20 business days.  An abbreviated 
regulatory review (i.e., reviewing protocol and consent versions, SAEs, PVs, DOA logs, 1572 
forms, etc.) will occur at each participant monitoring review; however, a full regulatory review 
will occur on a biennially basis by the DSMC for regulatory compliance. 
 
Auditing of all enrolled participants in these trials will be complete after 20% of enrolled 
participants have been audited through five cycles of treatment.  However, regulatory reviews of 
the trial, safety reviews (i.e., Serious Adverse Event (SAE) reviews and Protocol Violation (PV) 
reviews), and audit/inspection preparation (as applicable) will continue until the trial is closed by 
the IRB.   
 
 
 
 
 
 

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A.2.3 Review and Oversight Requirements 
 
A.2.3.a 
Adverse Event Monitoring  
 
All Grade 3-5 adverse events (AEs), whether or not considered to be expected or unexpected and 
whether or not considered to be associated with the use of the investigational agent(s) or study 
procedure, will be entered into OnCore®, UCSF’s Clinical Trial Management System.   
 
Adverse events are graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) as developed and revised by the Common Therapy Evaluation Program (CTEP) of the 
National Cancer Institute.  Adverse events are further given an assignment of attribution or 
relationship to investigational agent or study procedure.  Attribution categories are: 
 
• 
Definite – clearly related to the investigational agent(s) or study procedure. 
• 
Probable – likely related to the investigational agent(s) or study procedure. 
• 
Possible – may be related to the investigational agent(s) or study procedure. 
• 
Unrelated –clearly not related to the investigational agent(s) or study procedure. 
 
All Grade 3-5 adverse events entered into OnCore will be reviewed on a monthly basis at the Site 
Committee meetings.  The Site Committee will review and discuss the selected toxicity, the 
toxicity grade, and attribution assignment. 
 
A.2.3.b 
Serious Adverse Event Reporting  
 
By definition, an adverse event is defined as a serious adverse event (SAE) according to the 
following criteria: 
 
 
• 
Death 
• 
Life-threatening adverse experience* 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant disability/incapacity 
• 
Congenital anomaly/birth defect, or cancer, or 
• 
Any other experience that suggests a significant hazard, contraindication, side effect or 
precaution that may require medical or surgical intervention to prevent one of the 
outcomes listed above 
• 
Event that changes the risk/benefit ratio of the study.  
* A life-threatening adverse experience is any AE that places the patient or subject, in the view of 
the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include 
a reaction that, had it occurred in a more severe form, might have caused death. 
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported in 
accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported on a Med 
Watch form.   
 
UCSF IRB website for guidance in reporting serious adverse events: 
https://irb.ucsf.edu/adverse-event  

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Med Watch forms and information: 
www.fda.gov/medwatch/getforms.htm 
 
All serious adverse events are entered into OnCore, as well as submitted to the IRB (per IRB 
guidelines).  The SAEs are reviewed and monitored by the Data and Safety Monitoring Committee 
on an ongoing basis and discussed at DSMC meetings, which take place every six weeks.  The 
date the SAE is sent to all required reporting agencies will be documented in OnCore®.  
 
If the SAE involves a subject death, and is determined to be possibly, probably or definitely 
related to the investigational drug or any research related procedure, the event must be reported to 
the DSMC Chair (or Vice Chair) and DSMC Director within one business day.   
 
A.2.3.c        Review of Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert) is noted in the study, the Principal Investigator will notify 
the DSMC via report at the time the increased rate is identified.  The report will indicate if the 
incidence of adverse events observed in the study is above the range stated in the Investigator 
Brochure or package insert. 
 
If at any time the Investigator voluntarily holds enrollment or stops the study due to safety issues, 
the DSMC Chair (or Vice Chair) and the DSMC Director must be notified within one business day 
and the IRB must be notified as per IRB reporting regulations. 
 
A.2.3.d   Data and Safety Monitoring Committee Contacts: 
Katie Kelley, MD (DSMC Chair) 
415-353-9888 
Katie.kelley@ucsf.edu 
Box 3211 
UCSF HDFCCC 
San Francisco, CA 94158 
 
John McAdams (DSMC Director) 
415-476-8496 
John.mcadams@usf.edu 
Box0981 
UCSF HDFCCC 
San Francisco, CA 94158 
 
 
 

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 Appendix 3. Research blood procedures for collecting plasma for cannabinoid,  
endocannabinoid and inflammatory component (Plex-12 panel) analysis 
 
 
Supplies  
1. BD Vacutainer Cat # 367856 (Plasma tube,K2 EDTA 5.4 mg,13 x 75,3.0 mL) 
2. Nalgene cryogenic vial, 1.2 mL Millipore catalog number V4507. 
 
Procedure: 
1. Print barcode labels for specimen ID. Specimen ID should contain: subject identifier 
(subject name or study ID#), unique specimen ID, draw date and time. Print one label for 
the primary tube and each aliquot tube.  
2. If drawing blood specimen from an indwelling catheter, flush catheter with 20 mL of saline 
before and after obtaining blood. 
3. Draw 3mL of blood through the catheter and discard. 
4. Collect 4 to 6  mL of blood into a properly labeled lavender top vacutainer tube. 
5. Invert tube gently 8-10 times (rock slowing by hand).Place on ice. 
6. Centrifuge at 1800 RCF  for 8 minutes within 30 min of collection.  
7. Using a nonsterile pipette, aspirate the plasma, which appears as a clear-yellow liquid 
above the blood tissue layer. Place plasma into cryovial tubes as 1mL aliquots. 
8. Place aliquots into box/bag labeled with ID, visit, and visit date and freeze the plasma 
samples at -80oC until time of analysis. 
 
 
Shipping:  
Whole blood Will be aliquoted into cryovials, barcoded into the labs biorepository system, and stored 
at -80oC until analysis. 
The samples will be processed for analysis at the Center for Medicinal Cannabis Research (CMCR) 
and site should send samples to the following address: 
University of California, San Diego 
ATTENTION: CMCR Lab 
220 Dickinson Street, Suit B 
Mail Code8231 
San Diego, CA 92103-8231