Randomized, Double-blind Phase II Study of a Single Dose of Cannabidiol (CBD) for Acute Anticipatory Anxiety in Advanced Breast Cancer
Phase: PHASE2
Conditions: Advanced Breast Cancer, Anxiety, CBD
Sponsor: Dana-Farber Cancer Institute

1 
DF/HCC BIOMEDICAL PROTOCOL TEMPLATE 
Version Date:   
October 13, 2022 
 
 
Trial Registration ClinicalTrials.gov Identifier: NCT04482244 
NCI Protocol #:Not Applicable 
 
DF/HCC Protocol #: 19-886  
 
TITLE:  Randomized, Double-Blind Phase II Study of a Single Dose of Cannabidiol (CBD) 
Versus Placebo for Acute Anticipatory Anxiety in Advanced Breast Cancer   
 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute 
 
*Principal Investigator (PI): 
Ilana Braun, MD 
 
Dana-Farber Cancer Institute (DFCI) 
 
ibraun@partners.org 
 
Other Investigators: 
Peter Chai, MD 
 
Dana-Farber Cancer Institute  
 
pchai@partners.org 
 
 
William Pirl, MD 
 
Dana-Farber Cancer Institute  
 
William_pirl@dfci.harvard.edu 
 
 
Manan Nayak, PhD 
 
Dana-Farber Cancer Institute 
 
Manan_nayak@dfci.harvard.edu 
 
 
 
Stephanie Tung, MD 
 
Dana-Farber Cancer Institute 
 
stephanie_tung@dfci.harvard.edu 
 
Statistician: 
     Paul Catalano, Sc.D 
 
Dana-Farber Cancer Institute  
 
     pcata@jimmy.harvard.edu 
 
  
NCI-Supplied Agent(s): None 
Other Agent(s): cannabidiol (Epidiolex), commercial, GW Pharmaceuticals 
Study Exempt from IND Requirements per 21 CFR 312.2(b).   
 
Protocol Type / Version # / Version Date: Original, Version 1.9,  

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October 13, 2022 
 
 
 

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SCHEMA 
 
 
 
 

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TABLE OF CONTENTS 
 
SCHEMA 
3 
1. 
OBJECTIVES 6 
1.1 
Study Design ............................................................................................................6 
1.1 
Primary Objectives ...................................................................................................6 
1.2 
Secondary Objectives ...............................................................................................6 
2. 
BACKGROUND .................................................................................................................6 
2.1 
Study Disease(s).......................................................................................................6 
2.2 
IND Agent ................................................................................................................6 
2.3 
Rationale ..................................................................................................................8 
2.4 
Correlative Studies Background ..............................................................................9 
3. 
PARTICIPANT SELECTION .............................................................................................9 
3.1 
Eligibility Criteria ....................................................................................................9 
3.2 
Exclusion Criteria ..................................................................................................10 
3.3 
Inclusion of Women and Minorities ......................................................................11 
4 
REGISTRATION And Randomization PROCEDURES ..................................................11 
4.1 
General Guidelines for DF/HCC Institutions ........................................................11 
4.2 
Registration Process for DF/HCC Institutions .......................................................11 
4.3 
General Guidelines for Other Investigative Sites ..................................................11 
4.4 
Registration Process for Other Investigative Sites .................................................11 
5. 
TREATMENT PLAN ........................................................................................................12 
5.1. 
Treatment Regimen ................................................................................................12 
5.2. 
Pre-Treatment Criteria ...........................................................................................15 
5.3. 
Agent Administration .............................................................................................16 
5.4. 
General Concomitant Medication and Supportive Care Guidelines ......................17 
5.5. 
Criteria for Taking a Participant Off Protocol Therapy .........................................17 
5.6. 
Duration of Follow Up ...........................................................................................17 
5.7. 
Criteria for Taking a Participant Off Study ...........................................................17 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................18 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................18 
7.1. 
Expected Toxicities ................................................................................................19 
7.2. 
Adverse Event Characteristics ...............................................................................20 
7.3. 
Adverse Event Reporting .......................................................................................20 
7.4. 
Reporting to the Food and Drug Administration (FDA) .......................................21 
7.5. 
Reporting to Hospital Risk Management ...............................................................21 
7.6. 
Routine Adverse Event Reporting .........................................................................21 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................22 

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8.1. 
Cannabidiol (Epidiolex) .........................................................................................22 
8.2. 
Placebo ..................................................................................................................23 
9. 
STUDY CALENDAR .......................................................................................................26 
10. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................27 
10.1. Data Reporting .......................................................................................................27 
10.2. Data Safety Monitoring ..........................................................................................27 
11. 
STATISTICAL CONSIDERATIONS...............................................................................28 
11.1. Study Design/Endpoints.........................................................................................28 
11.2. Sample Size, Accrual Rate and Study Duration ....................................................28 
11.3. Stratification Factors ..............................................................................................29 
11.4. Interim Monitoring Plan ........................................................................................29 
11.5. Analysis of Primary Endpoints ..............................................................................30 
11.6. Analysis of Secondary Endpoints ..........................................................................30 
11.7. Reporting and Exclusions ......................................................................................30 
12. 
PUBLICATION PLAN .....................................................................................................30 
REFERENCES 
31 
 
 
 

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1. OBJECTIVES 
 
To test the preliminary efficacy of a single dose of oral cannabidiol (CBD) in reducing 
anticipatory anxiety in patients with advanced cancer poised to undergo computed tomography 
(CT) scan or positron emission tomography (PET) to assess tumor burden. 
 
Hypotheses 
A single dose of oral cannabidiol is superior to placebo in reducing anticipatory anxiety in 
advanced stage cancer patients with pre-existing anxiety poised to undergo CT or PET to assess 
tumor burden. 
1.1 
Study Design 
 
Randomized, double-blind, placebo-controlled trial of a single dose of CBD for anticipatory 
anxiety in advanced cancer patients. 
 
1.1 
Primary Objectives 
 
In patients with advanced cancer poised to undergo CT or PET to assess tumor burden, to 
evaluate the preliminary efficacy of oral CBD, as compared to placebo, in reducing anticipatory 
anxiety as measured by the “Afraid” subscale of the Visual Analog Mood Scale (VAMS).  
1.2 
Secondary Objectives 
 
To assess, using the Patient-Reported Outcomes version of the Common Terminology Criteria 
for Adverse Events (PRO-CTCAE™) and a qualitative assessment, patient–reported side effects 
and acceptability of taking oral CBD (versus placebo) for managing anticipatory anxiety. 
To evaluate whether CBD is superior to placebo in improving mood (as measured by VAMS 
subscales), nausea (as measured by the European Organisation for Research and Treatment of 
Cancer core quality of life questionnaire-nausea subscale) and pain levels (as measured by the 
Numeric Pain Rating Scale [NPRS]) 3(+/-1) hours after study agent administration in patients 
with advanced cancer. 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
Advanced breast cancer (stage IV or metastatic) 
 
2.2 
IND Agent 
 
The IND agent, cannabidiol (Epidiolex), is manufactured by GW Pharmaceuticals and is Federal 
Drug Administration (FDA)-approved for management of seizures associated with some form of 

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pediatric epilepsy in patients 2-years of age or older.1 Cannabidiol (Epidiolex) is a solution 
intended for oral consumption that contains, in addition to CBD (100 mg/mL), the following 
inactive ingredients: sesame seed oil, sucralose, alcohol and strawberry flavor.  
 
Cannabidiol (C21H30O2; molecular weight=314.46) is a non-intoxicating, non-addictive cannabis 
ingredient. A single clinical trial has been carried out in an oncology population. In this single-
arm phase II trial targeting graft-versus-host disease prophylaxis, CBD was found to be safe for 
use (and of promising effectiveness) in patients undergoing allogeneic hematopoietic cell 
transplantation2. Preclinical and clinical studies suggest that CBD possesses a variety of other 
therapeutic benefits with potential relevance to cancer patients. These include anxiolytic, 
antipsychotic, sedative, anticonvulsive, antiemetic, analgesic, and antitumor effects 3-6. Zeroing 
in on evidence regarding anxiolysis, using a cross-over model, Crippa et. al. demonstrated 
through subjective report, physiological parameter testing, and functional neuroimaging that 
CBD significantly ameliorates reactive anxiety in healthy normals (2004; N=10; anxiety 
provoking stimulus: MRI), those with generalized social anxiety disorder (2011; N=10), and 
those with social phobia N= 307. Although the agent’s mechanism of action has yet to be fully 
elucidated, 5HT1A receptor agonism is postulated to mediate such anti-anxiety effects5,7. 
 
In all human studies (including these), CBD is well-tolerated and, despite existing in the same 
plant as delta-9-tetrahydrocannabinol, manifests divergent and sometimes opposing effects3,5.  
For instance, in sharp contrast to delta-9-tetrahydrocanninol, CBD does not trigger abuse, 
dependence or withdrawal in preclinical studies. According to Epidiolex’s package insert, its 
most common adverse reactions-- based on chronic twice-daily dosing-- include somnolence, 
decreased appetite, diarrhea, fatigue, malaise, asthenia, rash, insomnia, sleep disorder, poor 
quality sleep, infection, and dose-related transaminase elevations. When they occur, 
transaminase elevations typically present in the first two months of use of the drug, and mainly 
in patients on concomitant valproate. In a third of patients, the transaminase elevations improve 
without intervention. In two-thirds, the transaminase elevations respond to reduction or 
discontinuation of CBD, valproate, or both. Like all antiepileptic drugs, CBD carries a warning 
to monitor for suicidal behavior; however, clinical data from the pediatric trials does not seem to 
demonstrate increase in suicidal behavior compared to patients on placebo. Epidiolex’s recent 
FDA approval, coupled with the United States Drug Enforcement Administration’s (DEA) 
descheduling, has openned doors to clinical trials of CBD in oncology.  
 
Preclinical models have demonstrated CBD to have a U-shaped dose response curve with respect 
to anxiety, with higher doses (20 or100 mg/kg) ineffective and lower dose CBD (10 mg/kg) 
effective5. In humans, 300-600 mg doses were found to have anxiolytic effects8. According to 
the Epidiolex package insert, CBD “demonstrate[s] an increase in exposure that [is] less than 
dose-proportional over the range of 5 to 20 mg/kg/day.” Cannabidiol has a time to maximum 
plasma concentration (Tmax) of 2.5-5 hours at steady state. The effects of food are significant: 
Taking CBD in the setting of a caloric, high-fat meal increases the Cmax 5-fold and the area under 
the curve (AUC) 4-fold. It also reduces the total variability, compared to the fasting state, in 
healthy volunteers. Cannabidiol’s volume of distribution in healthy volunteers is 20,963 L to 
42,849 L. Protein binding of the drug and its metabolites is >94% in vitro. The half-life of CBD 
in the plasma is 56-61 hours after a week of twice-daily dosing in healthy volunteers. Plasma 
clearance following a single 1500 mg CBD dose is 1111 L/h. Cannabidiol is metabolized by 

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CYP3A4 and CYP2C19. In the presence of moderate or strong inhibitors of these enzymes, dose 
reductions of CBD should be considered; in the presence of strong inducers, dose increases of 
CBD should be considered. Cannabidiol impedes metabolism of substrates of UGT1A9, 
UGT2B7, CYP2C8, CYP2C9, CYP2C19, and to an extent, CYP1A2 and CYP2B6. The 
somnolence and sedation experienced with CBD may be compounded by other central nervous 
system depressants such as alcohol or benzodiazepines. Of note, CBD is excreted in the feces 
with only mild renal clearance. 
 
2.3 
Rationale 
 
In the last half century, there have been few advances in the pharmacologic management of acute 
anxiety. As one example, a panic attack in 2019 is managed as it was in 1969: with a class of 
medications called benzodiazepines. While effective, benzodiazepines carry hefty risk profiles 
that include, acutely, cognitive slowing, even frank confusion, hypersomnia, perceptual 
disturbances, anterograde amnesia, accidental overdose, ataxia and hypotension, leading to falls 
and other injuries. Long-term benzodiazepine use may result in dependence, abuse, and a 
withdrawal reaction upon discontinuation.  
 
The lack of pharmacologic innovation in the management of acute anxiety is particularly 
concerning to oncology, where anxiety is ubiquitous. According to one study, 42% of cancer 
patients manifest clinical anxiety after cancer diagnosis9. Cancer-related concerns are myriad and 
include health and existential anxieties (for instance, after receipt of alarming test results), 
psychosocial worries (for instance, around the impact of cancer on occupation and family), and 
fears regarding procedures (for instance, chemotherapy infusions, surgeries and scans to assess 
tumor burden). Of note, the anxiety tied to radiographic procedures to assess tumor burden peaks 
prior to the actual scan (rather than during or after).10,11 While management strategies include 
relaxation techniques, psychological treatments such as counseling, and antidepressants, the 
mainstay of treatment for moderate to severe acute cancer-related anxiety remains 
benzodiazepines. Although rates of benzodiazepine use among cancer patients have not been 
published in the last three decades, previously published rates range from 16-25% 12 We suspect 
that current rates are higher, first because prescription benzodiazepine use is on the rise in the 
United States13 and, second, because the National Comprehensive Cancer Network now 
identifies benzodiazepines among the chief management strategies for anticipatory nausea and 
vomiting with chemotherapy14. Of note, the DFCI website prominently encourages use of 
benzodiazepines prior to radiographic imaging15. 
 
Common, however, is not necessarily good. The risks attending benzodiazepine use can be 
magnified in cancer patients who are more likely to be frail and elderly. In addition, 
benzodiazepine use prior to an oncology appointment in which important medical information is 
to be transmitted may impair patient comprehension and decision-making ability. In the general 
public and, especially, in cancer populations, safer, effective alternatives to benzodiazepines are 
warranted. 
 
Cannabidiol, a non-intoxicating, non-addictive cannabis ingredient, may confer similar benefits 
to benzodiazepines with fewer risks7,16. Preclinical and clinical studies suggest that CBD 
possesses anxiolytic, antipsychotic, sedative, anticonvulsive, antiemetic, anti-inflammatory, 

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analgesic, and antitumor effects 3-6. For instance, using a cross-over model, Crippa et. al. 
demonstrated through subjective report, physiological parameter testing, and functional 
neuroimaging that CBD significantly ameliorates reactive anxiety in healthy normals (2004; 
N=10; anxiety provoking stimulus: MRI), those with generalized social anxiety disorder (2011; 
n=10), and those with social phobia;7 n=30). Although the biochemical mechanism of 
cannabidiol has not yet been fully elucidated, 5HT1A receptors in limbic and paralimbic areas are 
postulated to mediate is anxiolytic effects7.   
 
In all human studies (including these), CBD was well-tolerated and, despite existing in the same 
plant as tetrahydrocannabinol, seems to have different and sometimes opposing effects to it 3,5. 
Administered acutely across a wide variety of oral (15 mg to 600 mg), intravenous (5 to 30 mg) 
and inhaled (0.15 mg/kg) doses, CBD produced no notable emotional, cognitive, psychomotor or 
vital sign side-effects7. Similarly, neither chronic administration up to 300 mg orally for 4.5 
months (n=15) nor, in a case report, 1500 mg/day for four weeks produced notable side-
effects17,18. In the case of the former, neurological and physical examinations, blood and urine 
analyses, electrocardiograms and electroencephalograms were performed at regular intervals. In 
fact, the United States Food and Drug Administration (FDA) recently approved pharmaceutical-
grade CBD manufactured by GW Pharmaceuticals under the trade name Epidiolex for 
management of forms of pediatric epilepsy. This approval, coupled with the United States Drug 
Enforcement Agency (DEA) descheduling of it has openned the door more widely to clinical 
trials of CBD in oncology.  
 
In this study we hope to test the preliminary efficacy of a single dose of oral cannabidiol (CBD) 
in reducing anticipatory anxiety in patients with advanced breast cancer. The inciting stressor in 
the study is anticipation of radiographic assessment of tumor burden. Research indicates that, in 
cancer patients undergoing positron emission tomography/computed tomography (PET/CT) 
scans, prescan anxiety is considerably elevated above post-precedure levels19 This finding is 
likely due to concerns about undergoing the procedure itself coupled with concerns about the 
prognostic results it may herrald19. Of note, no differences in anxiety amplitude were noted 
between patients who were naïve to the procedure and those who had undergone PET/CT 
previously19. 
 
2.4 
Correlative Studies Background 
 
N/A 
 
3. 
PARTICIPANT SELECTION 
 
3.1 Eligibility Criteria  
 
3.1.1 Diagnosis of Stage IV or metastatic breast cancer  
 
3.1.2 Age ≥18 years.   
 
3.1.3 Karnofsky ≥60%. 
 

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3.1.4 Participants must have adequate organ and marrow function at baseline as defined below: 
 
− 
total bilirubin 
 
<2 times institutional upper limit of normal (ULN) 
− 
AST(SGOT)/ALT(SGPT) 
 
≤3 × institutional ULN 
 
3.1.5 Baseline at least mild anxiety as measured by GAD-7 >5 
 
3.1.6 Experience of at least mild anxiety typically tied to anticipation of oncologic scans (as 
measured by a prescreen survey item)   
 
3.1.7 Computed tomography or positron emission tomography (PET) to assess tumor burden 
scheduled for within 48 hours of study drug administration 
 
3.1.8 No cannabis, delta-9-tetrahydrocannabinol or cannabidiol use within 24-hours of study 
drug administration. 
 
3.1.9 No benzodiazepine consumption within 8 hours of study drug administration (e.g., 
nighttime benzodiazepine use permissible) 
 
3.1.10 No driving for 12 hours following study drug administration. 
 
3.1.11 English proficiency 
 
3.1.12 The effects of cannabidiol (Epidiolex) on the developing human fetus are unknown. For 
this reason and because cannabis is known to be teratogenic, women of child-bearing 
potential must not be pregnant when entering the study. The study team will encourage 
women of child-bearing age to use adequate contraception (hormonal or barrier method 
of birth control; abstinence) prior to study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is pregnant while she is 
participating in this study, she should inform her treating physician immediately. Women 
must agree to use adequate contraception prior to the study, for the duration of study 
participation, and for 1 week after cannabidiol (Epidiolex) consumption. Women either 
age > 54 years, or  documented to be in menopause, or  status post hysterectomy will not 
be required to obtain bHCG. 
 
3.1.13 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to cannabidiol (Epidiolex) or placebo (which contains sesame, corn and 
gluten)  
 
3.2.2 Current clobazam or valproic acid use  
 
 

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3.2.3 Current uncontrolled illness, for instance sepsis, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia 
 
3.2.4 Current use of antiretroviral therapy 
 
3.2.5 Participants with psychiatric illness or social situations that would limit compliance with 
study requirements 
 
3.2.6 Current hepatocellular carcinoma or documented history of difficult to control diabetes 
 
3.2.7 Active participation in a clinical drug trial 
 
3.3 
Inclusion of Women and Minorities 
 
Women of all races and ethnic groups are eligible for this trial. Men will be excluded. 
 
4 
REGISTRATION AND RANDOMIZATION PROCEDURES  
 
4.1 General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. The randomization in this trial will be stratified on baseline 
anxiety level: Mild to moderate (5-14) versus Severe (15-21). 
 
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If the subject does not receive protocol therapy following registration, the 
subject must be taken off study in the CTMS (OnCore) with an appropriate date and reason 
entered.   
 
4.2 
Registration Process for DF/HCC Institutions 
 
Applicable DF/HCC policy (REGIST-101) must be followed and adobe e-sign for consent 
 
4.3 
General Guidelines for Other Investigative Sites 
 
Not Applicable 
 
4.4 Registration Process for Other Investigative Sites 
 
Not Applicable 

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5. TREATMENT PLAN 
 
5.1. Treatment Regimen 
 
5.1.1 Enrolling sites and study entry 
 
A sample of 200 participants who are scheduled undergo computed tomography (CT) scan or 
positron emission tomography (PET) to assess tumor burden will be recruited to a randomized 
control study in which they will receive a single dose of cannabidiol (Epidiolex) versus placebo.  
Accrued patients will continue on the study and will be randomized only if they meet the 
eligibility criteria at baseline (described below). Consenting and accrual will stop early if 50 
patients meeting eligibility (final sample needed for the study) are randomized and enrolled on to 
the study.   
 
A study team member will screen potential participants using the daily appointment logs of the 
DFCI Breast Oncology Center and the DFCI Department of Imaging. The study will also accept 
referrals from the Breast Oncology Program. We will also obtain a list of participants on 09-204, 
to aid in our recruitment activity.  We will present the study at patient forums; post study flyers 
in waiting rooms including virtual screens; post the study to DFCI websites (e.g., 
YAP@DFCI)distribute flyers at local cannabis dispensaries and cannabis certifiers to inform 
participants about the study (Appendix A: Study Letter & Recruitment Flyer). We will obtain a 
HIPAA waiver to enable medical record screening of potential participants. Once potential 
participants are identified, we will notify the primary oncologist of their patient’s eligibility via 
pager, email or in person. Providers need only contact the study team if they do not wish their 
patient to participate in the study.  
 
Study staff will approach the patient in clinic or schedule a virtual visit with the potential 
participants to introduce the study (Appendix A: Study Letter & Recruitment Flyer). They will 
assess eligibility and give potential participants time to ask questions and consider study 
participation. A licensed physician will answer questions and obtain consent from eligible 
participants (either in-person or remotely using Adobe eSign).  
 
Once inclusion criteria have been met and exclusions ruled out, study staff will follow the 
registering processes described in Section 4.0. Participants will be randomized in a 2:1 fashion to 
CBD or placebo using permuted blocks within strata and a double-blind procedure will be 
followed. Randomization will be completed by the Office of Data Quality (ODQ).  The 
eligibility checklist(s) and all pages of the consent form(s) will be faxed to the ODQ at 617-632-
2295. The ODQ will (a) review the eligibility checklist, (b) register the participant on the 
protocol, and (c) randomize the participant. 
 
All survey assessments will be completed either in-person or remotely (either through RedCap, 
phone, text messaging or by mail).  
  
Baseline: Following consent, if necessary (i.e., no such values exist in the chart within the last 6 
weeks +/- 7 days), the patient will complete laboratory assessments, as well as a series of 

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surveys. If during the course of these assessments, the patient is determined to not meet 
eligibility criteria, they will be taken off study.  Once the study team receives baseline 
assessment, the participant will be scheduled for Study Timepoint 1, which will take place within 
48 hours of the anticipated CT scan or positron emission tomography (PET) to assess tumor 
burden. Study staff will follow up via phone, email, and/or mail to remind the study participant 
of the scheduled study visit. 
 
Treatment Day:  
 
The Treatment Day will take place within 48 hours of anticipated CT scan or positron emission 
tomography (PET) to assess tumor burden (based on the study participant’s radiology 
appointment schedule). The study team will contact the participant approximately 24 hours 
before Timepoint 1 to ensure that the participant abstains from cannabis and benzodiazepine 
uses. Timepoint 1 (Pre-drug Administration Visit) will be completed prior to study drug 
administration. Observation for the drug administration is noted in section 5.3.  Timepoint 2 
(Post-drug Administration) will take place approximately 3(+/-1) hours following study drug 
administration.  In total the treatment day inclusive of timepoint 1 and timepoint 2 will be 
approximately 8 hours(+/-1). 
 
Timepoint 1 (Pre-drug Administration): Regardless of randomization arm, all participants will 
complete a set of questionnaires. The study team will review questionnaire responses assessing 
cannabis and benzodiazepine uses (e.g. section 3.1.8 & 3.1.9 of the eligibility criteria). If a 
participant indicates they have consumed either within the prohibited timeframe, the study team 
will attempt to delay study drug administration in order to meet eligibility criteria.  (Section 5 
offers full details on consuming study drug). However, if the study drug administration cannot be 
delayed, the Treatment Day will be rescheduled to coincide with the next scheduled CT scan or 
positron emission tomography (PET). See section 8.1.11. for unused study drug destruction. 
 
Timepoint 2 (Post-drug Administration): All participants will complete a set of questionnaires.  
 
Timepoint 3: Study staff will phone the participant within a week +/- 7 days of study drug 
consumption to conduct a brief, semi-structured audio-recorded interview.  
 
At study completion participants will receive a $50 gift card.  They will also receive up to $50 
for qualifying study-related travel costs and/or expenses.  After all study procedures are 
completed, the research team will contact participants to inform of which arm they were assigned 
after unblinding and share any publications that come from this study.   
 
 
5.1.2 Treatment Regimen 
 
Both arms: A physician researcher will order the trial drug. The research pharmacy will dispense 
cannabidiol (Epidiolex) versus placebo in a securely capped amber dosing syringe packaged in 
bubble wrap. The dose will be made available for pick-up or mailed. The Treatment Day will 
either occur on or off campus. Irrespective of the study arm to which the patient is assigned, the 
research team will ask study participants to refrain from consuming high-calorie or -fat meals for 

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one hour before and after study agent consumption. Examples of foods to avoid include those 
high in butter, cream, oil, cheese, whole milk, mayonnaise, salad dressing, jam, syrup, honey, 
nuts, as well as soft drinks, juices, sweets or desserts, pastas, breads, crackers, chips and meats. 
Reported adverse events and potential risks are described in Section 7.  Below outline specifies 
associated with individual arm.    
  
Cannabidiol (Epidiolex) arm: Cannabidiol (Epidiolex) is an FDA-approved commercially-
available oral solution that will be self-administered once in a 400 mg (4 mL) dose.  The study 
drug will be consumed within 5 minutes or less. There will be no observation period post dosing.  
No dose modifications will be necessary. Another dose will not be administered if the 
participants vomits after dosing. 
 
Placebo arm: The Dana-Farber Research Pharmacy will create the following non-sterile placebo 
formulation: Karo Light Corn Syrup and FLAVORx strawberry cream flavoring in a ratio 20 
ml:7 drops. Karo Light Corn Syrup consists of corn syrup, salt, vanilla extract (vanilla beans, 
water, ethyl alcohol). The strawberry cream flavoring is dye-free and safe for the following 
allergies: milk, egg, soybeans, peanuts, tree nuts, wheat, grain, fish, shellfish, seeds, latex and 
some dyes. A 4 mL dose of placebo will be self-administered once.   The study drug will be 
consumed within 5 minutes or less. There will be no observation period post dosing.  No dose 
modifications will be necessary. Another dose will not be administered if the participants vomits 
after dosing. 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Single Dose 
Route 
Schedule 
Cycle 
Length 
cannabidiol 
(Epidiolex) 
100mg/mL 
None 
 
400 mg (4 mL; since 
Epidiolex’s 
concentration is 
100mg/mL) 
 
PO  
Timepoint 1 
Within 
48 hours 
of CT or 
PET 
scan  
 
 
Placebo 
None 
 
400 mg (4 mL)  
PO  
Timepoint 1 
 
5.1.3 Instruments measuring study outcomes: 
 
Demographic questionnaire (Baseline): 
Variables of interest will be obtained via self-report and include: age, ethnicity, race, marital 
status, education, and occupational status.  
 
Cannabis History Questionnaire (Baseline): 
Cannabis use history will be obtained via self-report. 
 
Generalized Anxiety Disorder- 7 (GAD-7) (Baseline, Timepoint 1): The widely used and 
validated GAD-7 measures anxiety severity on a 4-point Likert-type scale from not at all to 

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nearly every day. The presence of baseline anxiety, as measure by a GAD-7 score >4, is 
necessary for inclusion in this study. 
 
Patient Health Questionnaire (PHQ-9) (Baseline, Timepoint 1): The widely used and validated 
PHQ-9 is a 9-item depression severity measure, with scores ranging from 0 to 27. Patients are 
asked to rate how they felt over the past two weeks using a 4-point Likert scale. Given that 
anxiety and depression are closely intertwined, this measure will help us to demonstrate that the 
active drug and placebo arms manifest similar levels of dysphoric distress. This measure will 
also help in screening to rule out “uncontrolled mental illness.” 
 
VAMS (Timepoint 1, and Timepoint 2): The Visual Analog Mood Scale (VAMS) a validated in-
the-moment measure of eight specific mood states: Afraid, Confused, Sad, Angry, Energetic, 
Tired, Happy, and Tense. Each scale consists of a 100 mm vertical line connecting a neutral face 
and a face displaying a particular mood state (with an accompanying descriptor). Subjects are 
asked to mark their mood along this continuum. The measure is scored using a metric ruler and 
the “Afraid” subscale will serve as our primary endpoint. Other subscales will serve as 
exploratory endpoints. 
 
EORTC-QLQc30-nausea (Timepoint 1, and Timepoint 2): The EORTC-QLQc30-nausea is a 
widely used and validated measure of symptom burden. It consists of 30-items, the first 28 of 
which employ a four-point scale (the final two are measured along a seven-point scale). Single 
item measures range in score from 0 to 100, with higher scores representing lower symptom 
burden. For the purposes of this study we will administer two items from the EORTC-QLQc30 
on nausea and vomiting to assess a secondary endpoint. 
 
Numeric Pain Rating Scale (Baseline, Timepoint 1, Timepoint 2): This widely used in-the-
moment pain intensity scale is scored from 0 to 10 (with 10 representing “worst possible” pain). 
The NPRS will again help us to assess secondary endpoints. 
 
Medical Record Review (Baseline, Timepoint 3): A member of the study team will record 
clinical data, including cancer diagnosis, disease stage, histology, and cancer treatments. 
Comorbidities or current medical history will also be extracted from medical records. 
 
5.2.Pre-Treatment Criteria 
 
5.2.1. Participants must have normal hepatic function at baseline as outlined below: 
 
− 
total bilirubin 
 
<2 times institutional upper limit of normal (ULN) 
− 
AST(SGOT)/ALT(SGPT) 
 
≤3 × institutional ULN 
− 
GAD-7 >5 
 
5.2.2. Cycle 1, Day 1 
− 
Karnofsky ≥60%. 
 
5.2.3. Subsequent Cycles  
 

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None 
 
5.3.Agent Administration 
 
Administration: Cannabidiol (Epidiolex), which comes in liquid form, is Federal Drug 
Administration-approved for rare forms of pediatric epilepsy.  We will use an oral dose of 400 
mg (4 mL) and will use this drug off-label for anxiety in adults with cancer.  Dose administration 
is well within the recommended daily dose per package insert.    
 
Dosing – This is a single dose study, with a dose of 400 mg (4 mL). Dose will be consumed 
within 5 minutes or less. Another dose will not be administered if the participants vomits after 
dosing. There will be no observation period post dosing.   
 
Special Equipment – Disposable 10mL oral syringe with secured cap will be dispensed and either 
picked up, shipped, or delivered to the patient. The patient will then self-administer the 
cannabidiol (Epidiolex) using the oral syringe. 
 
Oral Agents – Participants will be advised to avoid consuming high fat meals for one hour before 
and after study drug consumption. Examples of foods to avoid include those high in butter, 
cream, oil, cheese, whole milk, mayonnaise, salad dressing, jam, syrup, honey, nuts, as well as 
soft drinks, juices, sweets or desserts, pastas, breads, crackers, chips and meats. No other 
protocol specific procedures are necessary. 
 
Caregiver Precautions – Study participants should not operate heavy machinery for 12 hours 
post study drug consumption. 
 
5.3.1. CTEP and/or CIP IND Agent(s), or other IND agent 
None 
 
5.3.2. Other Agent(s)Placebo 
 
Administration: The Dana-Farber Research Pharmacy will create the following non-sterile 
placebo liquid formulation: Karo Light Corn Syrup and FLAVORx strawberry cream flavoring 
in a ratio 20 ml:7 drops. We will use an oral dose of 4 mL.  
 
Dosing – This is a single dose study, with a dose of 400 mg (4 mL). Dose will be consumed 
within 5 minutes or less. Another dose will not be administered if the participants vomits after 
dosing. There will be no observation period post dosing.   
 
Special Equipment – A disposable 10mL oral syringe with secured cap will be dispensed and 
either picked up, shipped or delivered to the patient. The patient will then self-administer the 
placebo using the oral syringe. 
 
Oral Agents – Participants will be advised to avoid consuming high fat meals for 1 hour before 
and after study drug consumption. Examples of foods to avoid include those high in butter, 
cream, oil, cheese, whole milk, mayonnaise, salad dressing, jam, syrup, honey, nuts, as well as 

NCI Protocol #: 
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17 
soft drinks, juices, sweets or desserts, pastas, breads, crackers, chips and meats. No other 
protocol specific procedures are necessary. 
 
Caregiver Precautions – Study participants should not drive or operate machinery for 12 hours 
post study drug consumption. 
 
5.3.3. Other Modality(ies) or Procedures 
 
N/A 
 
5.4. 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of cannabidiol (Epidiolex) with other concomitantly 
administered drugs through the cytochrome P450 system, a licensed physician on the study team 
will review participants list of medication prior to study drug administration.  
 
5.5. 
Criteria for Taking a Participant Off Protocol Therapy 
 
The planned duration of therapy is a single day. Treatment will be halted in the setting of: 
 
• Inability to ingest study medication on the day of study 
• Intercurrent illness that prevents administration of treatment 
• Unacceptable adverse event(s) 
• Participant demonstrates an inability or unwillingness to comply with the oral medication 
regimen and/or documentation requirements 
 
• Participant decides to withdraw from the protocol therapy 
• General or specific changes in the participant's condition render the participant 
unacceptable for treatment in the judgment of the treating investigator 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
When a participant is removed from protocol therapy and/or is off of the study, the participant’s 
status must be updated in OnCore in accordance with REGIST-OP-1. 
 
5.6. 
Duration of Follow Up 
 
Participants will be followed for approximately 1 week after removal from protocol therapy or 
until death, whichever occurs first.  Participants removed from protocol therapy for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event. 
 
5.7. 
Criteria for Taking a Participant Off Study 
 

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Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
• Investigators discretion 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure the 
participant’s status is updated in OnCore in accordance with REGIST-OP-1. 
 
There will also be a protocol around emergency unblinding. In this double-blind study, the 
research pharmacy not be blinded. Unblinding will occur when knowledge of the treatment is 
essential for the emergency management of a serious adverse event (SAE) as defined in section 
7.1. Unblinding of the study for other reasons will be considered a major protocol violation. The 
PI must be notified if unblinding of a patient is necessary. The PI has designated the 
responsibility of unblinding to the MD’s only. MD requesting this will notify and discuss with PI 
either by phone or email and when approved by the PI, the treating MD will notify the research 
pharmacy. An email will be sent to the research pharmacy at DFCIPharmacyIDS@partners.org 
with the protocol number, the patient name, MRN, the reason for the unblinding, and indicating 
the PI’s approval. The DFCI research pharmacy will send the unblinded information back to the 
MD and receipt of the email will be acknowledged by the MD. During off hours, weekends, and 
holidays, the pharmacy administrator on call will be paged via the DFCI page operator at 617-
632-3737 from within DFCI, or 617-632-3352 from outside DFCI. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
This is a single dose study, therefore dosing delays are not allowed or applicable. There will be 
no modifications to the dose of cannabidiol (Epidiolex) or placebo given to study participants. 
Although there are recommended dose adjustments in individuals with hepatic dysfunction, these 
individuals are excluded from the study.   
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. Because this study is being completed in an advanced illness 
population, deaths due to cancer are expected. The research team will not report cancer-related 
deaths as adverse events. 
 
The principal investigator will be responsible for monitoring and reporting all adverse events to 
the DFCI IRB for this study, but in the event that the principal investigator is unavailable, the co-
investigators will assume this responsibility. The role of the responsible person is to 1) identify 
the concern, 2) develop the appropriate response to the concern with the use of consultants if 
necessary and 3) ensure proper reporting of concerns to the IRB.  
 

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All potential adverse events will be reported to the PI. The PI in consultation with Co-
investigators will classify events according to level of severity. Details will be recorded on an 
adverse case report form as well as logged on a secure spreadsheet for reporting to the IRB.  
 
The adverse event case report form will include a description of all undesirable experiences, 
required interventions, and an assessment of the subject after the event if possible.  An estimate 
of the extent of injury, and prevention strategies will be reported. The principal investigator will 
classify the relationship of the study protocol to the event as follows: 
• Not related: The event is clearly related to factors such as the subject’s clinical state, not 
with the study protocol. 
• Remote: The event was most likely related to factors such as the subject’s clinical state, not 
with the study protocol. 
• Possible: The event follows a reasonable temporal sequence associated with participating in 
the study and/or is consistent with events related to responding to queries about stress/drug 
craving but is possibly related to factors such as the subject’s clinical state. 
• Probable: The event follows a reasonable temporal sequence associated with participating 
in the study and/or is consistent with events related to dosing of cannabidiol (Epidiolex) in 
the study and cannot be reasonably explained by factors such as the subject’s clinical state. 
The severity of an adverse event in both groups is defined as a qualitative assessment of the 
degree or intensity of an adverse event as determined by the principal investigator as 
follows: 
• Mild: No impact (in anyway) on the subjects. 
• Moderate: Impacts on the subject but is not life-threatening or incapacitating. 
• Severe: Fatal, life threatening, permanently disabling; severely incapacitating; 
requires/prolongs inpatient hospitalization. 
 
7.1. 
Expected Toxicities 
 
7.1.1. Adverse Events List(s) for cannabidiol (Epidiolex) 
The most likely adverse event from single dose cannabidiol (Epidiolex) in this investigation 
is somnolence. Although we will ask study participants to refrain from benzodiazepine use 
between study visits 2 and 3, participants may still use benzodiazepines while not under the 
study team supervision. Combination of benzodiazepine plus cannabidiol (Epidiolex) may 
result in somnolence. No reports of hypopnea or respiratory arrest have been described with 
cannabidiol (Epidiolex). Please refer to attached commercial package insert for details and 
comprehensive list of adverse events. They include: 
 
• nonfatal hepatotoxicity 
• seizures 
• suicidal ideation or behavior 
• nausea and vomiting 
 
7.1.2. Adverse Events List(s) for Placebo 
 
• none 

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7.1.3. Adverse Events List(s) for PHQ-9 
 
• 
Any participant who evidences potential suicidal ideation on the PHQ-9 will be evaluated 
by one of the study’s psychiatrists or referred a psycho-oncologist in the Department of 
Psychosocial Oncology and Palliative Care for such clinical evaluation. 
 
 
7.2. 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version  5.0.  A copy of the CTCAE version  5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3. 
Adverse Event Reporting  
 
7.3.1. In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the Overall PI. 
 
7.3.2. Investigators must report to the Overall PI any adverse event (AE) that occurs after the 
single dose of study drug, or within 30 days of the single dose of study drug on the local 
institutional SAE form.  
 
7.3.3. DF/HCC Adverse Event Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 

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7.3.4. Protocol-Specific Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting to 
the Overall PI or the DFCI IRB.  However, they still must be reported through the routine 
reporting mechanism (i.e., case report form). 
 
 
 
CTCAE SOC 
Adverse 
Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Comments 
Allergic 
Reaction 
 
1,2 
 
 
 
Alanine 
aminotransfera
se increased 
 
1, 2 
 
 
 
Aspartate 
aminotransfera
se increased 
 
1, 2 
 
 
 
Ataxia 
 
1, 2 
 
 
 
Cognitive 
disturbance 
 
1 
 
 
 
Dizziness 
 
1, 2 
 
 
 
Lethargy 
 
1 
 
 
 
Agitation 
 
1, 2 
 
 
 
Confusion 
 
1 
 
 
 
Depression 
 
1, 2 
 
 
 
 
7.4. 
Reporting to the Food and Drug Administration (FDA) 
 
Not applicable since FDA deemed this IND exempt. 
 
7.5. 
Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports, sentinel events or unanticipated problems that require reporting per institutional 
policy.  
 
7.6. 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 

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8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7.1. 
 
8.1. 
Cannabidiol (Epidiolex) 
 
8.1.1. Description 
 
Cannabidiol (Epidiolex) is an herbal-derived phytocannabinoid. The molecular formula is 
C21H30O2. The molecular weight is 314.46. After oral administration, the time to maximum 
concentration (Cmax) is 2.5-5 hours. In individuals who have recently ingested a high fat diet, 
the Cmax increases by 5-fold. Cannabidiol is protein-bound but has a volume of distribution of 
20963-32849L. After twice daily dosing, the half-life of cannabidiol is 56-61 hours. Cannabidiol 
is hepatically metabolized via CYP2C19 and 3A4 to 7-OH-CBD. 7-OH-CBD is the major 
metabolite and remains pharmacologically active. Metabolites of cannabidiol undergo fecal-
elimination. A secondary route of elimination is renal. Cannabidiol is a substrate for CYP 2C19 
and 3A4 and inhibitor of 1A2 and 2B6. A minor metabolite, 7-COOH-CBD is a PgP substrate. 
Major drug interactions include concomitant use of clobazam and valproic acid. 
Coadministration of clobazam with CBD results in increased 7-OH-CBD levels. 
Coadministration of valproic acid with CBD has no effect on valproate levels, but the 
combination may result in reversible hepatic injury.  
 
8.1.2. Form 
 
Cannabidiol (Epidiolex), manufactured by GW Pharmaceuticals, is a clear (colorless to yellow) 
solution intended for oral consumption. In addition to CBD (100 mg/mL), it contains sesame 
seed oil, sucralose, alcohol and strawberry flavor.  
 
8.1.3. Storage and Stability 
 
Cannabidiol (Epidiolex) should be stored at room temperature 20 to 25°C (68 to 77 °F)  in its 
original bottle and in an upright position. Excursions are permitted between 15 to 30°C (59 to 
86°F). Once opened, Cannabidiol has a shelf life of 84 days. The oral solution may be kept in the 
syringe for up to 24 hours. For this reason the medication will be overnighted to patients. 
 
 
8.1.4. Compatibility 
 
Not Applicable 
 
8.1.5. Handling 
 
This is commercially available and no special handling considerations are necessary. 
 

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8.1.6. Availability 
 
Cannabidiol (Epidiolex) is commercially available and the DFCI pharmacy will purchase the 
drug on behalf of our research team. The study will cover the cost for Epidiolex. 
 
8.1.7. Preparation 
 
Cannabidiol (Epidiolex) at the appropriate dose will loaded into syringe labeled “Cannabidiol or 
Placebo” (or something similar). 
 
8.1.8. Administration 
 
Disposable 10mL oral syringe will be used to administer cannabidiol (Epidiolex) PO at the 
conclusion of Timepoint 1.  
 
8.1.9. Ordering 
 
Cannabidiol (Epidiolex), which is commercially available, will be obtained through GW 
Pharmaceuticals. The study drug will be shipped to and logged at the investigational pharmacy at 
DFCI. The research pharmacy will dispense the study drug either directly to the participant or to 
the study staff for mailing. Patient drug accountability will be ensured through self-report in the 
form of query on Study Day Timepoint 2 (Appendix H). 
 
8.1.10. Accountability 
 
The investigator, or a responsible party designated by the investigator, will maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
8.1.11. Destruction and Return 
 
Expired or unused supplies of cannabidiol or placebo will be destroyed according to institutional 
guidelines. Destruction will be documented in the Drug Accountability Record Form. If the 
study drug is in possession of the study participant and they are unable to take the drug during 
the time period. We will ask the participant to return the unused investigational drug for 
destruction and log this on our internal drug tracking log. 
 
8.2. 
Placebo 
 
8.2.1. Description 
 
The Dana-Farber Research Pharmacy will create the placebo as follows: a non-sterile formula of 
Karo Light Corn Syrup and FLAVORx strawberry cream flavoring in a ratio 20 ml:7 drops. Karo 
Light Syrup consists of salt, vanilla extract (vanilla beans, water, ethyl alcohol). 
 

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8.2.2. Form 
 
Formulated by the Dana-Farber Research Pharmacy, the placebo is a non-sterile, caramel-
colored solution intended for oral consumption, containing Karo Light Corn Syrup and  
FLAVORx strawberry cream flavoring in a ratio 20 mL:7 drops. The strawberry cream flavoring 
is dye-free and safe for the following allergies: milk, egg, soybeans, peanuts, tree nuts, wheat, 
grain, fish, shellfish, seeds, latex and some dyes.  
 
8.2.3. Storage and Stability 
 
Placebo should be stored at room temperature (68 to 77 F) in a bottle kept in an upright position. 
FLAVORx has an expiry date on the stock bottle. The oral solution may be kept in the syringe 
for up to 24 hours. For this reason the medication will be overnighted to patients. 
 
8.2.4. Compatibility 
 
Not applicable 
 
8.2.5. Handling 
 
No special handling considerations are necessary. 
 
8.2.6. Availability 
 
The Dana-Farber Research Pharmacy will purchase the components of the placebo, which are 
commercially available, on behalf of our research team. The study will cover the cost for 
placebo. 
 
8.2.7. Preparation 
 
An appropriate dose of the placebo will be loaded into syringe labeled “Cannabidiol or Placebo” 
(or something similar). 
 
8.2.8. Administration 
 
Disposable 10mL oral syringe will be used for patients to self-administer placebo PO.  
 
8.2.9. Ordering 
 
Components of the placebo are commercially available, and various manufacturers may be used 
to purchase the product by Dana-Farber Research Pharmacy. The components of the placebo will 
be logged at the investigational pharmacy at DFCI. The research pharmacy will dispense the 
placebo either directly to the participant or to the study staff for mailing. Patient drug 
accountability will be ensured through self-report in the form of query on Study Day Timepoint 
2 (Appendix H). 
 

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8.2.10. Accountability 
 
The investigator, or a responsible party designated by the investigator, will maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
8.2.11. Destruction and Return 
 
Expired or unused supplies of cannabidiol or placebo will be destroyed according to institutional 
guidelines. Destruction will be documented in the Drug Accountability Record Form.  
 
 
 

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9. STUDY CALENDAR 
 
  
Baseline 
assessment 
Timepoint 1 
Treatment day, 
pre-assessment 
Timepoint 2 
Treatment day, 
post-assessment 
Timepoint 3  
Follow-up 
assessment  
Prior to 
Timepoint 1 
Within 48 hours of 
a CT/PET scan to 
assess tumor 
burden 
3 (+/- 1) hour post 
ingestion 
<1-week (+/- 7 
days) post 
ingestion 
Background Information 
  
Informed consent*** 
X 
  
  
  
Screener questionnaire 
X 
 
 
 
Demographics 
X 
  
  
  
Medical history 
X 
  
X  
Concurrent medications 
X 
X 
  
  
Performance status 
X 
  
  
LFTs 
X 
  
  
  
bHCG** 
X 
  
  
  
GAD-7 
X 
X 
  
  
PHQ9 
X 
X 
  
  
Cannabis History 
Questionnaire 
X 
 
 
 
Cannabidiol (Epidiolex) vs. 
Placebo 
 
X* 
 
 
Confirmation of study drug 
consumption 
 
 
X 
 
Patient Provisions  
 
 
 
 
$50 gift card 
 
 
 
X 
Primary endpoints 
  
VAMS afraid subscale 
X 
X 
  
Secondary endpoints 
  
  
  
  
NPRS 
X  
X 
X 
  
EORTC-QLCc30-nausea 
X 
X 
  
Other subscales of VAMS 
X 
X 
  
Qualitative interview 
  
  
X 
Safety Monitoring 
  
Adverse Event Evaluation 
  
X 
X 
* = Study drug to be administered after completion of Treatment day, pre-assessments 
**= bHCGs will be collected on all potential participants under the age of 54-years, unless known to be post-menopausal or status post 
hysterectomy 
*** = to be completed with physician involvement 
 
 

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10. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
10.1. Data Reporting 
 
10.1.1. Method 
 
The study staff will collect, manage, and perform quality checks on the data for this study. 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and participant-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis, either by FTP burst of data or via the CDS web application.  Reports 
are due January 31, April 30, July 31, and October 31.  Instructions for submitting data using 
the CDUS can be found on the CTEP Web site  
(http://ctep.cancer.gov/reporting/cdus.html).    
 
10.1.2. Responsibility for Data Submission 
 
Participant institutions are responsible for submitting CDUS data and/or data forms to either the 
Coordinating Center or to the Lead Organization on the study quarterly.  The date for submission 
to the Coordinating Center or to the Lead Organization will be set by them.  CDUS does not 
accept data submissions from the participant institutions on the study.  When setting the dates, 
allow time for Coordinating Center compilation, Overall PI review, and timely submission to 
CTEP by the quarterly deadlines (see Section 12.1.1).  For trials monitored by CTMS, a 
quarterly report of data will be provided by Theradex to the Coordinating Center. 
 
Either the Coordinating Center or the Lead Organization is responsible for compiling and 
submitting CDUS data to CTEP for all participant institutions and for providing the data to the 
Overall PI for review.   
 
10.2. Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor study 
progress, toxicity, safety and other data from this study. The Board is chaired by a medical 
oncologist from outside of DF/HCC and its membership composed of internal and external 
institutional representation. Information that raises any questions about participant safety or 
protocol performance will be addressed by the Overall PI, statistician and study team. Should 
any major concerns arise, the DSMB will offer recommendations regarding whether or not to 
suspend the study. 
 
The DSMB will meet twice a year to review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMB may include: participant accrual; 
treatment regimen information; adverse events and serious adverse events reported by category; 
summary of any deaths on study; audit results; and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request.  

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11. STATISTICAL CONSIDERATIONS 
 
This is a phase II, randomized, placebo-controlled study to assess the preliminary efficacy of 
offering a single dose of CBD versus placebo in reduction of anxiety in patients with advanced 
(stage IV) solid tumor anticipating CT to assess tumor burden. Eligible patients must have 
measurable anxiety-- at least “mild” anxiety as measured by the GAD-- at the pre-screen visit.  
 
Anxiety level at each of the time points (pre-screening visit, pre-dose, and 3[+/-1] hour post 
dose) will be plotted for each study group. The paired change (pre-dose to post-dose) in anxiety 
will be estimated along with a 95% confidence interval for each study group. The change in 
anxiety will be compared by study group with a Wilcoxon rank sum test. The side-effect profile, 
as measured by the PRO-CTCAE will be tabled according to side effect. Patient reported 
experience with CBD and the acceptability will be summarized with descriptive statistics and 
qualitative methodology as appropriate 
 
11.1. Study Design/Endpoints 
 
Primary Endpoint 
Change in anxiety will be assessed by the Visual Analog Mood Scale (VAMs) anxiety subscale, 
ascertained on the day of the drug administration pre-dose (T1) and 3(+/- 1) hour after drug 
administration (T2). The change in anxiety score will be calculated for each patient and a 
Wilcoxon rank sum test will be used to assess whether the change score is different among 
patients randomized to CBD as compared to placebo.      
 
Secondary and Exploratory Endpoints  
Secondary and exploratory objectives include a description of the side-effect profile of CBD in 
oncology patients, patient reported experience and acceptability of CBD, and the estimation of 
the change in state anxiety as well as other VAMs subscales (Afraid, Confused, Sad, Angry, 
Energetic, Tired, Happy, and Tense). Secondary endpoint analyses will be considered 
exploratory (no alpha adjustment given the relatively small sample size) and will provide context 
for interpretation of the primary endpoint. 
 
Randomization 
Patients will be randomized 2:1 to CBD or placebo using permuted blocks within strata (one 
single stratification variable, baseline anxiety with 2 levels, will be used) and a double-blind 
procedure will be followed. Randomization will be completed by the Office of Data Quality 
(ODQ). ODQ will send the randomization assignment to the DFCI Research Pharmacy and the 
pharmacy will dispense the medication. The justification for the 2:1 randomization is to better 
assess side-effects and to allow for more qualitative data at the completion of the study. 
 
 
11.2. Sample Size, Accrual Rate and Study Duration 
 
 
 

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Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
8 
+ 
0 
= 
8 
Not Hispanic or Latino 
192 
+ 
0 
= 
192 
Ethnic Category: Total of all subjects 
200 
(A1) + 
0 
(B1) = 
200(C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
4 
+ 
0 
= 
4 
Black or African American 
4 
+ 
0 
= 
4 
Native Hawaiian or other Pacific 
Islander 
0 
+ 
0 
= 
0 
White 
192 
+ 
0 
= 
192 
Racial Category: Total of all subjects 
200 
(A2) + 
0 
(B2) = 
200(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
The Visual Analog Mood Scale (VAMs) anxiety subscale is measured on a 0 to 100 scale and is 
then converted to a T-score standardized by age and gender. The VAMs manual suggests that, in 
a pre-test/post-test setting, a score differing by 20T indicates a reliable change in mood and a 
score differing by 30T indicates a reliable and clinically meaningful change in mood20. Studies 
comparing depressed and non-depressed psychiatric patients indicated possible standard 
deviations ranging from 15-3620.  Additionally, a previous study18 demonstrated that the change 
from pre-dose to 140 minutes post-dose in the VAMs anxiety subscale was approximately 16.7 
for CBD and 3.5 for placebo respectively in 10 subjects with social anxiety disorder. In the same 
sample, the reported standard deviations pre- and post- CBD ranged from approximately 7 to 15. 
 
A two-sided, Wilcoxon rank sum test will be used to assess the difference in change in anxiety 
score between CBD and placebo. Estimating a minimal change in anxiety for patients assigned to 
placebo, a difference in the change score of 20 is be targeted. Assuming a two-sided significance 
level of 0.05, a 2 to 1 randomization, and a standard deviation of 20, there is 80% power to 
detect a difference of 20 (effect size = 1) in the change in anxiety score between CBD and 
placebo with 45 patients (30 CBD, 15 placebo). Based on an approximated 10% attrition rate, 50 
patients will be enrolled and randomized. 
 
11.3. Stratification Factors 
 
Randomization will be stratified on baseline anxiety level, mild to moderate (5-14) versus severe 
(15-21). 
 
11.4. Interim Monitoring Plan 
 
N/A 
 

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30 
11.5. Analysis of Primary Endpoints 
 
Please see above. 
 
11.6. Analysis of Secondary Endpoints 
 
This will be an intent-to-treat analysis. Secondary endpoint analyses will be considered 
exploratory and will provide context for interpretation of the primary endpoint.  
 
11.7. Reporting and Exclusions 
 
11.7.1. Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment. 
 
11.7.2. Evaluation of the Primary Efficacy Endpoint 
 
Sub-analyses may then be performed on the basis of a subset of participants, excluding those for 
whom major protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol violations, etc.).  However, these sub-analyses 
will not serve as the basis for drawing conclusions concerning treatment efficacy, and the 
reasons for excluding participants from the analysis will be clearly reported.  If applicable to the 
endpoint, the 95% confidence intervals will also be provided.  
 
12. PUBLICATION PLAN 
 
The results will be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  
 
At the end of the trial, PI will contact ODQ/research pharmacy and obtain randomization 
assignments.  
 
 
 
 
 
 
 
 
 

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Version Date: November 19, 2021 
 
31 
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