Pilot Study of Ketamine-assisted Talk Therapy for Demoralization in Advanced GI Cancer
Phase: PHASE4
Conditions: Pancreatic Ductal Adenocarcinoma, Pain, Acute, Gastrointestinal Cancers, Demoralization
Sponsor: Brian Anderson, MD

Proprietary and Confidential
The information in this document is considered privileged and confidential and may not be disclosed to others except to the 
extent necessary to obtain Institutional Review Board approval and informed consent, or as required by federal and state 
laws.  Persons to whom this information is disclosed should be informed that this information is privileged and confidential 
and that it should not be further disclosed. 
Pilot study of ketamine-assisted talk therapy for 
demoralization in advanced GI cancer
Protocol Number: CC# 238011
Investigational Product(s):  Ketamine
Version Number:  2.5
Version Date:  November 07, 2024
IND Number: 166544
NCT Number: 
06077487
Principal Investigator (Sponsor-Investigator)
Brian T. Anderson, MD, MSc
University of California, San Francisco
Co-Principal Investigator
Andrea Rosati, MD, PhD
 University of California, San Francisco
Statistician
Joan F. Hilton, DSc, MPH
Revision History
Version 2.5
11-07-2024
Version 2.4
10-14-2024
Version 2.3
08-25-2024
Version 2.2
04-18-2024
Version 2.1
03-22-2024
Version 2.0
03-13-2024
Version 1.9
01-22-2024
Version 1.8
10-27-2023
Version 1.7
08-22-2023
Version 1.6
08-08-2023
Version 1.5
07-21-2023
Version 1.4
06-23-2023
Version 1.3
06-08-2023
Version 1.2
05-16-2023
Version 1.1
01-22-2023
Version 1.0
09-23-2022

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Protocol Signature Page
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review and Monitoring 
Committee (PRMC), Institutional Review Board (IRB), and Data and Safety Monitoring 
Committee (DSMC). 
2.
I will conduct the study in accordance with the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices 
(GCP) and the applicable IRB, ethical, federal, state, and local regulatory requirements. 
3.
I certify that I, and the study staff, have received the required training to conduct this research 
protocol. 
4.
I agree to maintain adequate and accurate records in accordance with IRB policies, federal, 
state and local laws and regulations.
Signature of UCSF Principal Investigator
Date
Name of UCSF Principal Investigator (Printed)

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Abstract
Title
Pilot study of ketamine-assisted talk therapy for demoralization in 
advanced GI cancer
Study Description
This is a single-site, parallel-arm double-blind randomized controlled pilot 
trial (N=12) of 0.5mg/kg oral ketamine vs. 0.5mg/kg intramuscular 
ketamine, each administered as a single dose, in combination with 4 
sessions of Meaning and Purpose therapy (MaP), for adults diagnosed 
with stage 3 or 4 gastrointestinal (GI) cancers (i.e., primary pancreatic, 
colorectal, hepatocellular, biliary, and gastro-esophageal cancers) who 
have moderate-to-severe demoralization. The combination of ketamine 
and Meaning and Purpose therapy will be referred to as K-MaP. 
MaP is a brief, existential behavioral intervention. It is a form of talk 
therapy designed to help patients cope with demoralization through a 
review of the patient’s value and worth, their key relationships, and 
sources of fulfillment and meaning in life [1]. Participants will have 2 
sessions of MaP before drug administration, and 2 sessions after drug 
administration. The expected study duration from enrollment to study 
completion is up to 63 days for each participant.     
Demoralization is a clinically significant and measurable form of 
existential distress characterized by poor coping and a sense of 
helplessness, hopelessness, and a loss of meaning and purpose in life [2, 
3].  Demoralization will be measured by Demoralization Scale-II (DS-II), a 
validated measure [4]. The scale includes 16 items, the total score range 
is 0-32, and a score of 10 or higher indicates moderate-to-severe 
demoralization [4, 5]. DS-II will be assessed at baseline, after 2 sessions 
of MaP but before ketamine, and then 1, 2, and 5 weeks after ketamine. A 
change in the DS-II of at least 2 points has been considered clinically 
meaningful in palliative care patients and will be used as a minimum point 
reduction indicative of efficacy [4]. 
Phase of Study
Pilot
Investigational 
Products
Ketamine
Study population
Adult  stage 3 and 4 GI cancer patients with moderate to severe 
demoralization.
Primary Objective
To assess the feasibility of Meaning and Purpose therapy combined with 
ketamine (K-MaP) in demoralized patients.

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Secondary 
Objectives
1.
To characterize the preliminary safety and tolerability of K-MaP in 
demoralized patients with stage 3 and 4 GI cancers.
2.
To assess the magnitude and durability of improvement from 
randomization in psychosocial distress.
3.
To assess the magnitude and durability of improvement from 
randomization in pain.
4.
To assess the magnitude of change from randomization in opioid 
analgesic use.
5.
To assess the magnitude and durability of change from randomization 
in interoceptive awareness. 
Sample Size
12 patients, 6 patients per arm.
Arm A: (0.5 mg/kg of ketamine, PO)
Arm B: (0.5 mg/kg of ketamine, IM)
Duration of Study 
Treatment
Ketamine will be given once on Day 0/Visit 4.
Patients will receive MaP therapy 4 times, twice before ketamine 
administration (Day 0), and twice afterward:
1.
Day -13 to -4/Visit 2
2.
Day -12 to -1/Visit 3
3.
Day 3 (+/- 2 days)/Visit 5
4.
Day 11 (+/-2 days)/Visit 7
The duration of treatment for K-MaP therapy (ketamine and MaP) is 
approximately up to 28 days.
Duration of Follow 
up
Patients will be followed up to 35 days (+/-2 days) after ketamine 
administration.

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Study Schema 

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List of Abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMP
Basic Metabolic Panel
BPI-SF
Brief Pain Inventory-Short Form
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CEQ
Challenging Experience Questionnaire
CMP
Comprehensive Metabolic Panel
CNS
central nervous system
CR
complete response
CRF
case report form
C-SSRS
Columbia Suicidality Severity Rating Scale
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTMS
Clinical Trial Management System
DFS
disease-free survival
DLT
Dose-limiting toxicity
DS-II
Demoralization Scale II
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECG/EKG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
FACIT-
Pal-14
Functional Assessment of Chronic Illness Therapy Palliative Care 14 Item Version
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
GAD7
General Anxiety Disorder-7
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBcAb
hepatitis B core antibody
HC Ab
hepatitis C antibody

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List of Abbreviations
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HBD
HIPAA
Heartbeat Detection Task
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
IA
ICF
Interoceptive accuracy
Informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IDS
Investigational Drug Services (UCSF)
IND
investigational new drug application
IP
investigational product
IRB
Institutional Review Board
IV
intravenous
K-MaP
Ketamine and Meaning and Purpose
MaP
Meaning and Purpose
MEQ
Mystical Experience Questionnaire
MME
Morphine Milligram Equivalents
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
ORR
overall response rate
PD
disease progression
PDAC
pancreatic ductal adenocarcinoma
PHQ9
Patient Health Questionnaire-9
PK
pharmacokinetics
PO
Per os (by mouth, orally)
PR
partial response
PRMC
Protocol Review and Monitoring Committee (UCSF)
RR
SC
SD
Respiration rate
Skin conductance
stable disease
UP
Unanticipated problem

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Table of Contents
Abstract
3
List of Abbreviations...................................................................................................................6
Table of Contents.......................................................................................................................8
1
Introduction...................................................................................................................10
1.1
Background on Indication.................................................................................10
1.2
Background on the Investigational Product(s) and Associated Known 
Toxicities ..........................................................................................................10
1.3
Rationale for the Proposed Study .....................................................................13
2
Study Objectives ..........................................................................................................15
2.1
Hypothesis ........................................................................................................15
2.2
Primary Objective and Endpoint(s) ..................................................................15
2.3
Secondary Objectives and Endpoints ...............................................................15
2.4
Exploratory (Correlative) Objectives................................................................17
3
Study Design................................................................................................................17
3.1
Characteristics...................................................................................................17
3.2
Sample Size.......................................................................................................18
3.3
Eligibility Criteria.............................................................................................18
3.3.1
Inclusion Criteria ..........................................................................................18
3.3.2
Exclusion Criteria .........................................................................................20
3.4
Inclusion and Recruitment of Women and Minorities......................................21
3.4.1
Eligibility of Women and Minorities............................................................21
3.5
Inclusion Across the Lifespan...........................................................................21
3.5.1
Age Range of Participants ............................................................................21
3.5.2
Study Design/Recruitment Considerations Related to Age Groups .............21
3.6
Duration of Treatment ......................................................................................22
3.7
Duration of Follow Up......................................................................................22
3.8
Randomization Procedures ...............................................................................22
3.9
Primary Completion..........................................................................................22
3.10
Study Completion .............................................................................................22
4
Investigational Products ...............................................................................................22
4.1
Description, Supply and Storage of Investigational Products ..........................22
4.1.1
Ketamine.......................................................................................................22
4.2
Accountability Records for Investigational Product(s) ....................................23
4.3
Ordering Investigational Product......................................................................23
5
Treatment Plan.............................................................................................................24
5.1
Dosage and Administration ..............................................................................27
5.1.1
Rescue Medications ......................................................................................28
6
Study Procedures and Schedule of Events..................................................................28
6.1
Study Calendar..................................................................................................32
7
Participant Registration ................................................................................................36
7.1
Use of Concomitant Medications .....................................................................36

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Table of Contents
7.2
Dietary Restrictions ..........................................................................................36
7.3
Prohibited Medications.....................................................................................37
7.4
Evaluation of Safety..........................................................................................37
8
Safety Parameters........................................................................................................37
8.1
Definitions ........................................................................................................37
8.1.1
Adverse Event (AE)......................................................................................37
8.1.2
Serious Adverse Event (SAE).......................................................................37
8.1.3
Unanticipated Problem (UP).........................................................................38
8.2
Classification of Adverse Events......................................................................38
8.2.1
Severity .........................................................................................................38
8.2.2
Attribution.....................................................................................................38
8.2.3
Expectedness.................................................................................................39
8.3
Recording of Adverse Events ...........................................................................39
8.4
Expedited Reporting .........................................................................................39
8.4.1
Reporting to the HDFCCC Data and Safety Monitoring Committee...........39
8.4.2
Reporting to Institutional Review Board ......................................................39
8.4.3
Expedited Reporting to the FDA ..................................................................39
8.5
Follow-up of Adverse Events ...........................................................................40
8.6
Adverse Events Monitoring..............................................................................40
9
Statistical Considerations and Evaluation of Results ...................................................40
9.1
Sample Size Considerations..............................................................................40
9.1.1
Sample Size and Power Estimate..................................................................40
9.1.2
Randomization ..............................................................................................40
9.1.3
Accrual Estimates .........................................................................................40
9.2
Analyses Plans..................................................................................................41
9.2.1
Population for Analysis.................................................................................41
9.2.2
Primary Analysis (or Analysis of Primary Endpoints) .................................41
9.2.3
Secondary Analysis (or Analysis of Secondary Endpoints) .........................41
9.3
Pre-study Documentation .................................................................................42
9.4
Institutional Review Board Approval...............................................................43
9.5
Informed Consent .............................................................................................43
9.6
Changes in the Protocol....................................................................................43
9.7
Handling and Documentation of Clinical Supplies ..........................................43
9.8
Case Report Forms (CRFs)...............................................................................43
9.9
Oversight and Monitoring Plan.........................................................................44
9.10
Record Keeping and Record Retention ............................................................44
9.11
Publications.......................................................................................................45
10
References...................................................................................................................46
Appendix 1
Palliative Performance Scale v. 2 (PPSv2)[111].............................................52
Appendix 2
Data and Safety Monitoring Plan ....................................................................53

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1
Introduction
1.1
Background on Indication
Patients with advanced-stage gastrointestinal (GI) cancers—including pancreatic, gastro-
esophageal, colorectal, hepatocellular, and biliary cancers—often face significant psychological 
distress due to the aggressive nature of these malignancies, poor prognoses, and challenging 
treatment regimens [6-19]. Among the various forms of psychological distress, demoralization—a 
clinically significant and measurable [22, 23] form of existential distress characterized by poor coping 
and a sense of helplessness, hopelessness, and a loss of meaning and purpose in life [2, 24]—has 
been increasingly recognized as a significant concern in this population. Demoralization is 
associated with physical symptom burden and poor quality of life, and it is highly prevalent (13-73%) 
among patients with serious medical illness (e.g., advanced cancer)  [25-30]. In patients with cancer, 
demoralization is often more strongly associated with suicidal ideation than is major depressive 
disorder (MDD) [31, 32]. Prevalence rates of clinically significant demoralization among end-of-life 
and palliative care (EOLPC) patients is typically reported as 20-30% when using the two most widely 
used measures for this condition—the Demoralization Scale (DS, a patient-reported outcome) and 
the Diagnostic Criteria in Psychosomatic Research (DCPR, a clinician-rated assessment) [33-36]. 
Previous studies involving patients with progressive disease (including GI malignancies) have 
demonstrated a strong positive correlation between demoralization and depression, respectively 
measured by the Demoralization Scale-II (DS-II) and Patient Health Questionnaire-9 (PHQ-9) 
surveys [33, 37].. 
Given the high prevalence of demoralization among patients with GI cancers and the limitations of 
existing treatments, there is a critical need for novel therapeutic approaches. Currently, no 
medication has an FDA indication for the treatment of demoralization, and no FDA-approved 
medications have been reliably shown to improve demoralization. Several psychotherapies have 
been shown to produce small-to-moderate treatment effects on psychosocial distress in EOLPC 
patients [39, 40]. These interventions often involve weeks of individual or group psychotherapy, 
treatment effects are often measured only in comparison to waitlist controls or treatment-as-usual 
(TAU), and treatment allocation typically cannot be masked. For example, in one of the largest 
(n=321) and best-designed trials of an existential psychotherapy for EOLPC patients, Breitbart et al. 
showed that, for patients with advanced cancer, 7 sessions of Meaning-Centered Psychotherapy 
(MCP) produced statistically significant improvements (with small-to-medium effect sizes) in spiritual 
well-being, meaning-in-life and quality of life when compared to enhanced usual care; but there were 
no statistically significant effects when MCP was compared to supportive psychotherapy [41]. When 
Kissane et al. administered 6-sessions of the existential psychotherapy, Meaning and Purpose 
therapy (MaP), to 45 advanced cancer patients in an exploratory pilot study (with no inclusion 
criterion based on degree of distress at baseline) they found no meaningful pre-post improvement in 
demoralization by the DS-II (Cohen’s d = 0.16, 95% CI -0.29, 0.86) [42]. In a relatively large RCT 
(n=305) of outpatient oncology patients, Rodin et al. compared usual care (UC) alone with UC plus 
Managing Cancer and Living Meaningfully (CALM)—an attachment- and existential-based 
psychotherapy [43]. Participants in the active treatment arm were supposed to receive 3-6 sessions 
of CALM therapy over 3-6 months, with at least 3 sessions by month 3. The effect size for the 
between-groups difference (Cohen’s d) in improvement from baseline on the 24-item Demoralization 
Scale was negligible at 3- and 6-months. Only in a subgroup analysis of patients with moderate 
death anxiety at baseline did the authors find effect sizes for improvement in demoralization of d = 
0.1 and d = 0.5 at 3- and 6-months, respectively.
1.2
Background on the Investigational Product(s) and Associated Known 
Toxicities
Ketamine is a centrally-acting NMDA glutamate receptor antagonist that is a DEA Schedule 3 
medicine and FDA-approved as a dissociative anesthetic. Esketamine (the s-stereoisomer of 

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ketamine) was approved by the FDA in 2019 for treatment-resistant depression. Ketamine is used 
widely for procedural sedation and is frequently used off-label for chronic pain and psychiatric 
disorders, including depression and anxiety. The use of ketamine for treatment of depression is 
supported by specialty medical societies including the American Psychiatric Society and the 
American Society of Ketamine Physicians, Psychotherapists, and Practitioners. The UCSF Lexicomp 
label lists depression as an indication for ketamine. Ketamine therapy for psychiatric illness is 
offered widely in California, including by the SF Veterans Administration Medical Center, UCLA, and 
UCSD. The UCSF P&T committee approved use of ketamine for depression in June 2018. 
This section of text is excerpted from the UCSF UpToDate Lexicomp on Ketamine:[44] 
Ketamine is a racemic mixture of two enantiomers, S-ketamine and R-ketamine. 
Ketamine is a standard anesthetic drug that is also administered for analgesia and 
sedation [2,3]. In addition, ketamine and esketamine can rapidly and transiently alleviate 
treatment-resistant unipolar major depression, including suicidal ideation [4,5]. For 
unipolar major depression, the efficacy of ketamine and esketamine appear to be 
comparable [1]. However, no head-to-head trials comparing the two drugs have been 
published.
The optimal method of administering ketamine for treatment resistant depression has not 
been established [26]. Although most studies have given ketamine intravenously, it can 
also be administered with intramuscular, intranasal, oral, subcutaneous, and sublingual 
formulations [2,12,25,27-29]. 
For treatment-resistant depression, repeated administration of oral ketamine can provide 
short-term improvement. A small, three-week randomized trial compared add-on oral 
ketamine 1 mg/kg with placebo in patients receiving usual care (n = 40) [25]. Most of the 
patients had melancholic features and comorbid psychopathology. Response (reduction 
of baseline symptoms ≥50 percent) occurred in more patients who received active drug 
than placebo (32 versus 6 percent). The number needed to treat was approximately four, 
meaning that for every four patients treated with ketamine and every four treated with 
placebo, one additional response occurred with ketamine. Follow-up assessments one 
week after treatment found that the benefit of ketamine persisted. In addition, adverse 
effects were mild and transient.
The dose of ketamine for treatment-resistant depression varies depending upon the 
route and frequency of administration [26,29]. For any particular route of administration, 
no one dose has been established among the different doses tested.
It appears that ketamine can be used concurrently with most standard antidepressants 
without reducing efficacy or increasing side effects [37]. Across randomized trials, 
ketamine has been administered either as monotherapy or as add-on therapy to 
antidepressants and antipsychotics [4,16,25,34,36,38-40]. 
Ketamine is metabolized primarily by hepatic cytochrome P450 2B6 and 3A4 [37]. 
Concomitant drugs that induce these enzymes may decrease exposure to ketamine and 
drugs that inhibit these enzymes may increase exposure; these effects may necessitate 
adjusting ketamine doses. 
Adverse effects — Adverse effects such as psychotomimetic effects may occur more 
often with ketamine than with esketamine [1]. However, no head-to-head trials comparing 
the two drugs have been published.

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One review of adverse effects in patients treated for resistant depression 
with ketamine found that side effects occur more often with ketamine than placebo or 
active controls [12]. However, most side effects resolved spontaneously.
Short term — Short-term ketamine for treatment-resistant depression is generally safe 
and well tolerated [6,29,35,66]. In a pooled analysis of three randomized trials, which 
called for either a single infusion of intravenous ketamine 0.5 mg/kg over 40 minutes or 
multiple infusions over a 12-day period, 97 patients received a total of 205 infusions [35]. 
During the 205 infusions, early discontinuation due to adverse effects (hypertension, 
anxiety, or hypotension) occurred in 2 percent.  
For patients with treatment-resistant depression who receive intravenous ketamine, side 
effects peak within two hours [3]. In short-term studies (e.g., ≤30 days), transient adverse 
effects included:
Dissociation and psychotomimetic effects – A review of 60 studies (randomized trials 
and observational studies with nearly 900 patients) found that dissociation and 
psychotomimetic effects were reported in more than 70 percent of the studies [12]. 
Studies of intravenous ketamine were two times more likely to report dissociation and 
psychotomimetic effects than non-intravenous studies.
Randomized trials, which typically administered a single intravenous dose of ketamine, 
indicate that ketamine causes significant, clinically large dissociative and 
psychotomimetic effects at 40 to 60 minutes after initiating infusion, which subsequently 
resolved within four hours [4,6,36,38,40,45]. In one trial that administered repeated 
infusions for up to four weeks, the intensity of dissociative symptoms appeared to 
diminish with repeated infusions [36]. Results from another trial suggest that dissociation 
occurs in a dose response manner. (See 'Intravenous' above.)
Multiple randomized trials studying ketamine for treatment-resistant depression have 
excluded patients with psychotic features [16,25,28,34-36,40,56].
Cardiovascular – A review of 60 studies (randomized trials and observational studies) 
found that nearly 40 percent of the studies described cardiovascular changes [12]. In 
randomized trials, which typically administered a single intravenous dose of ketamine, 
hemodynamic effects included time-limited increases in blood pressure and heart rate:
Systolic blood pressure – In four randomized trials, mean increases in systolic blood 
pressure ranged from 8 to 19 mmHg within 40 minutes of infusion, which normalized in 
four hours or less [4,16,40]. In a pooled analysis of three randomized trials that included 
97 patients who received a total of 205 infusions, the transient average peak increase 
was 20 mmHg [35].
Diastolic blood pressure – In a pooled analysis of three randomized trials that included 
97 patients who received a total of 205 infusions, the transient average peak increase in 
diastolic blood pressure was 13 mmHg [35]. Two subsequent randomized trials found 
that mean increases ranged from 8 to 13 mmHg within 40 minutes of infusion, which 
normalized in two hours or less [16,40].
In addition, a retrospective study included 66 patients with a mean age of 57 years who 
received an average of 10 ketamine infusions, 0.5 mg/kg over 40 minutes [69]. Essential 
hypertension controlled by pharmacotherapy was present in 36 percent. An increase in 
systolic pressure >30 mmHg or in diastolic pressure >15 mmHg during at least one 
infusion occurred in 50 percent of the patients. Nearly 80 percent of the blood pressure 

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elevations occurred 30 to 40 minutes after onset of the infusion, and all of the elevated 
readings resolved within 70 minutes of onset.
Pulse – In one randomized trial, the mean heart rate increased by 9 beats/minute within 
two hours of infusion, which subsequently normalized [16].
Results from randomized trials suggest that elevated blood pressure and pulse occur at 
higher doses in a dose response manner. (See 'Intravenous' above.)  
Other cardiovascular changes that may occur include chest pain, palpitations, and/or 
pressure, which generally resolved within 90 minutes of receiving ketamine [12].
Other – Other common, transient adverse effects of ketamine in randomized trials 
included [36,40,53]:

Anxiety

Blurred vision

Dizziness

Headache

Nausea or vomiting
End of text is excerpted from the UCSF UpToDate Lexicomp on Ketamine:[44]
1.3
Rationale for the Proposed Study
Ketamine has demonstrated efficacy for the treatment of depression, suicidality, and pain in non-
cancer patients [45-48]. Multiple case series demonstrate that ketamine has promise for the 
treatment of psychosocial distress, suicidality, and pain in the hospice setting, but more research is 
needed among distressed patients with cancer [49-52]. Pre-clinical and clinical data suggest that 
ketamine modulates glutamate-mediated neural circuits implicated in mood disorders, such as 
depression and demoralization [53, 54].
This study is designed to assess the feasibility and preliminary safety and efficacy of oral vs. 
intramuscular ketamine, in conjunction with a manualized talk therapy, as a treatment for patients 
diagnosed with advanced GI cancers and moderate-to-severe demoralization. This double-blinded 
pilot study will assess the effects of two different doses and routes of ketamine administration 
(0.5mg/kg PO and 0.5mg/kg IM) in patients with advanced GI cancer, providing data that can be 
used to optimize ketamine treatment for this patient population. 
Several prior clinical trials have demonstrated that ketamine treatment is safe and effective for 
treatment-resistant depression, and esketamine is now FDA-approved for this purpose. This study 
offers an opportunity to explore the utility of this therapy among demoralized GI cancer patients 
using a ketamine formulation which is FDA-approved for other indications using two different routes 
of administration (PO and IM) that may be more accessible and tolerable than the more extensively 
studied intravenous (IV) and intranasal (IN) routes of ketamine administration.  
There are minor risks involved in this study. Generally, oral and IM ketamine are safe and well-
tolerated. As noted above, transient increases in systolic blood pressure and heart rate occur in a 
minority of patients receiving this therapy. Patients may experience transient anxiety and/or 
dissociative effects. All of these effects are dose dependent. Study participants will be monitored 
continuously throughout the ketamine treatment session and followed closely in the weeks afterward 
in their subsequent talk therapy sessions. 
Rationale for Dose Selection

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We will test two different doses and routes of ketamine administration: 0.5mg/kg PO and 0.5mg/kg 
IM. These doses were selected on the basis of existing data. As a safety precaution, we will use a 
maximum limit of oral ketamine of 60 mg, given that higher doses have not been evaluated in clinical 
trial settings in the U.S.
Case series and one published clinical trial of oral ketamine as a treatment of depression in patients 
with advanced cancer have shown that a daily oral dose of 0.5mg/kg is well-tolerated and briefly 
improved depression symptoms [55-57]. An ongoing trial of weekly oral ketamine for anxiety in 
patients with pancreatic ductal adenocarcinoma (PDAC) is using a dose of 0.5mg/kg PO [58]. The 
bioavailability of oral ketamine is estimated to be 10-17% [59].
Clinical trials investigating the use of intramuscular ketamine for the treatment of depression in 
palliative populations and the general public have used starting doses ranging from 0.1mg/kg - 
1.0mg/kg IM [60-62], all of which have been reported to be relatively well-tolerated. The 
bioavailability of intramuscular ketamine is 93% [63, 64].Similar or higher doses of ketamine are 
frequently used in various clinical settings. Many trials of IV ketamine for unipolar depression have 
used a dose of 0.5mg/kg administered as a slow infusion [65], while one survey of n=98 community 
clinics administering off-label ketamine for psychiatric conditions uses doses ranging from 0.5-
3.0mg/kg IV [66]. A retrospective study of n=420 patients receiving IM ketamine for depression found 
starting doses ranging from 0.3 - 2.15mg/kg IM, with a median starting dose of 0.55mg/kg IM [67]. A 
second case series of n = 40 patients utilized a protocol involving a starting dose of ketamine 
1.0mg/kg IM, divided into two 0.5m/kg IM doses spaced 15 minutes apart [68]. In a recent 
systematic review of ketamine in palliative care populations, patients were most commonly started at 
starting doses of ketamine 0.5mg/kg SC or IV [69]. Another survey of three ketamine clinics (two of 
which are in the San Francisco Bay Area) provided data on n=253 patients treated with off-label 
ketamine-assisted psychotherapy using sublingual administration (with a bioavailability of 15-25%) at 
doses of 25-400 mg, and often in the range of 200-250 mg [70]. Finally, in an FDA-related abuse 
liability study published in 2011, 100 mg of oral ketamine was used as a control drug for the 
serotonin 2C receptor agonist lorcaserin [71].
Additionally, a previous protocol by colleagues at UCSF (CC#20807, PI: Dr. Brieze Bell) obtained 
UCSF IRB approval, pending FDA approval, for a dosing regimen of ketamine 1.67mg/kg sublingual 
(SL) during an initial Ketamine session, with dose escalation up to 3.3mg/kg SL at subsequent 
Ketamine sessions. Note: This trial was not initiated due to being on FDA clinical hold pending the 
production of Chemistry Manufacturing and Control data for the novel sublingual formulation. 
Correcting for bioavailability, our study’s oral and intramuscular ketamine doses are lower than those 
proposed in the Dr. Bell’s protocol, but equal to or greater than those from the above-mentioned 
ongoing trial of oral ketamine to treat anxiety in PDAC patients [58].
Volume of distribution and terminal clearance of ketamine do not differ by age, disease state, route 
of administration (oral, intramuscular, subcutaneous, inhaled, intranasal, intravenous), administration 
form (S- or RS-ketamine), or analyte (S-, R- or RS-ketamine), suggesting that one set of ketamine 
PK parameters may be used to determine dosing in a variety of conditions by any route of 
administration [72]. Thus, the safety profile of oral ketamine is expected to be like that of any other 
route of administration. The FDA-approved drug label for intravenous/intramuscular ketamine 
(Ketalar) includes that the liquid formulation may be administered intravenously with an initial dose in 
the range of 1-4.5 mg/kg or intramuscularly at doses of 6.5-13 mg/kg. The bioavailability of ketamine 
is 93% for intramuscular injection and only 17% for oral administration [64]. Per the ketamine drug 
label, regarding intravenous administration, “the average amount required to produce 5 to 10 
minutes of surgical anesthesia within 30 seconds following injection is 2 mg/kg.” Therefore, 
extrapolating from this amount of ketamine, the average 70 kg person would be administered 140 
mg intravenously, and sometimes repeatedly if further doses were needed. Thus, our proposed 

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doses of oral and intramuscular ketamine, each at 0.5 mg/kg, will result in significantly lower levels 
of drug exposure than what is already permitted by the ketamine drug label for surgical anesthesia. 
2
Study Objectives 
2.1
Hypothesis
We hypothesize that K-MaP therapy is safe and feasible for administration to patients with advanced 
GI cancers with moderate-to-severe demoralization. In addition, we hypothesize that stage 3 and 4 
GI cancer patients will tolerate K-MaP therapy, and patient experiences during K-MaP therapy may 
result in improvements from randomization in measures of psychosocial distress, pain, opioid 
analgesic use, and interoceptive awareness.
2.2
Primary Objective and Endpoint(s)
Primary Objective
Endpoint(s)
Time Frame
To assess the feasibility of 
Meaning and Purpose 
therapy combined with 
ketamine (K-MaP) in 
demoralized patients with 
advanced GI cancers.
1. Rate of recruitment (i.e., proportion 
enrolled and fully eligible vs screened 
participants).
2. Proportion of enrolled participants 
completing (i) K-MaP intervention 
(receiving ketamine, all four Meaning 
and Purpose therapy sessions) and (ii) 
all DS-II assessments, by arm.
3. Qualitative review of clinician fidelity to 
manualized K-MaP intervention.
4. Qualitative feedback on acceptability to 
participants of the intervention and 
assessments (20-minute interview with 
participants upon study termination), by 
arm.
1. From time of 
screening to 
enrollment.
2. From Day -28 to 
Day 14 (about 28 
days).
3. From Day -14 to 
Day 14 (about 28 
days).
4. On Day 35.
2.3
Secondary Objectives and Endpoints
Secondary Objective
Endpoint(s)
Time Frame

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1.
To characterize the 
preliminary safety and 
tolerability of K-MaP in 
patients with stage 3 and 4 
GI cancers. 
1. Adverse events (AEs), Unexpected 
AEs, and Serious AEs, by CTCAE (v.5.0).
2. Vital signs (heart rate and blood 
pressure)
3. Patient-reported outcome: challenging 
experiences (CEQ)  
1.
Day -28 
through Day 
35.
2.
Day 0 
(multiple 
time points 
on day of 
ketamine 
administratio
n).
3.
Day 0, 3-4 
hours after 
ketamine 
administratio
n.
2.
To assess the magnitude 
and durability of 
improvement from 
randomization in 
psychosocial distress.
1.
Clinician-rated outcomes: Global 
clinical impression of 
severity(CGI-S), Demoralization 
(DI), Mood symptoms (GRID-
HAMD-6).
2.
Patient-reported outcomes: 
Demoralization (DS-II), 
Depression (PHQ9), Anxiety 
(GAD7), Quality of Life (FACIT-
Pal-14).
From Day -28 to 
Day 35.
3.
To assess the magnitude 
and durability of 
improvement from 
randomization in pain.
Patient-reported outcome: pain (BPI-SF) 
From Day -28 to 
Day 35.
4.
To assess the magnitude of 
change from randomization 
in opioid analgesic use.
Patient-reported outcome: Opioid use 
(<24hr morphine milligram equivalence 
[MME])
From Day -28 to 
Day 35.
5.
To assess the magnitude of 
change from randomization 
in interoceptive awareness. 
Patient-reported outcome: interoceptive 
awareness (MAIA-2) 
From Day 0 to Day 7

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2.4
Exploratory (Correlative) Objectives
Exploratory Objective
Endpoint(s)
Time Frame
1.
To assess how the 
participants’ subjective 
experiences with ketamine 
may be related to clinical 
outcomes.
Patient-reported outcome: Subjective 
reports of participants’ ketamine 
experiences on Day 0 will be transcribed, 
inductively coded and analyzed to identify 
phenomenological content that may be 
related to clinical outcomes
Patient-reported outcome: Challenging 
and mystical experience questionnaire 
(CEQ and MEQ) scores correlated with 
changes in reported measures of 
demoralization (DS-II), pain (BPI-SF), and 
opioid use (MME).
Day 0
From Day -28 to 35. 
2.
To assess how the 
participants’ changes in 
measures of cardiac 
interoception following 
receipt of ketamine may be 
related to subjective 
experiences with ketamine 
and clinical outcomes. 
Patient-reported outcome: Changes in 
scores on a heartbeat detection task 
(HBD) conducted before and after 
ketamine correlated with scores on the 
mystical experience questionnaire (MEQ) 
as well as changes in reported measures 
of interoceptive awareness (MAIA-2), 
demoralization (DS-II), pain (BPI-SF), and 
opioid use (MME). 
From Day -28 to 35.
3
Study Design
3.1
Characteristics
This is a parallel-arm, double-blind, randomized controlled pilot trial (N=12) of two different dose levels 
of ketamine administered as a single dose, in combination with 4 sessions of Meaning and Purpose 
therapy (MaP) for stage 3 and 4 GI cancer patients (including those with primary pancreatic, 
gastroesophageal, hepatocellular, biliary, and colorectal malignancies) experiencing moderate-to-
severe demoralization. 
Demoralization is a clinically significant and measurable form of existential distress characterized by 
poor coping and a sense of helplessness, hopelessness, and a loss of meaning and purpose in life [2, 
3]. Demoralization will be measured by Demoralization Scale-II (DS-II), a validated measure [4]. The 
scale includes 16 items, and a total score of 10 or higher indicates moderate-to-severe demoralization.
Participants will be administered 2 sessions of MaP before drug administration, and 2 sessions after 
drug administration. The combination of ketamine and Meaning and Purpose therapy will be referred 
to as K-MaP.
Adult  GI oncology patients at HDFCCC and other Bay Area medical centers will be referred by their 
clinical teams. Referred patients must demonstrate clinically significant and stable demoralization as 
measured by DS-II ≥10/32 two times ≥7 days apart (both during screening) to be eligible for the study. 
The first measurement of the DS-II scale will occur over the phone. After a verbal waiver of consent, 

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the study team will read the questions to the potential participant, and the potential participant’s 
answers will be recorded by the study team. If the score is ≥10/32, the study team will talk to the 
participant about joining the study. The data from the phone screen will only be used for screening 
and will not be used as research results. The second DS-II measurement will be given to the participant 
in person after they have signed the informed consent form on the day of enrollment (i.e. baseline, 
between Day -28 and -7). The DS-II questions will be administered to the patient either on paper or 
electronically with a tablet (using REDCap). Following best practices with patient-reported outcomes 
[73], participants will fill out the second DS-II without clinician or study staff involvement. In the event 
that a participant has a question about how to fill out the questionnaire, study staff will be trained only 
to read the instructions printed at the top of the measure or to assist the participant with reading a 
particular item, but staff will say nothing beyond reading the wording on the instrument itself. The DS-II 
will be scored by summing the responses to all 16 items to generate a total score. Participants must 
score a 10 or higher in order to be eligible for the study. 
If the participant meets all of the eligibility criteria, they will be randomized 1:1 on Day 0 to one of two 
cohorts (0.5 mg/kg of ketamine PO or 0.5 mg/kg of ketamine IM). The study is double-blinded, meaning 
neither the study participants nor the study investigators will know which dose of ketamine each 
participant is receiving. Participants randomized to receive ketamine 0.5 mg/kg PO will receive an 
equivalent quantity of normal saline (placebo) via an intramuscular injection after ingesting oral 
ketamine, and those who are randomized to receive ketamine 0.5 mg/kg IM will receive their IM 
injection after ingesting an equivalent quantity of normal saline (placebo) orally. Orally administered 
ketamine and normal saline (placebo) will be mixed in cranberry juice immediately prior to being 
administered to the patient.  
K-MaP will consist of 4 sessions of Meaning and Purpose (MaP) therapy and a single dose of ketamine 
on Day 0. Two MaP sessions will occur prior to ketamine therapy at least 2 days apart, the 1st session 
between Days -13 and -4, and the second session between Days -12 and -1. The two sessions of 
MaP after ketamine administration will occur on Days 3 (+/- 2 days) and 11 (+/- 2 days). All five 
intervention visits will be booked at the participant’s baseline visit (see Study Schema). 
3.2
Sample Size
We estimate an enrollment rate of 1-2 participants per month, for an enrollment period lasting 6 
months. It is expected that approximately 50% of patients being referred to the study will meet 
eligibility criteria at the time of screening. The study team thus aims to screen 24 or more potential 
participants. 
3.3
Eligibility Criteria
3.3.1
Inclusion Criteria
In order to be eligible to participate in this study, an individual must meet all of the following criteria:
1.
Must have a diagnosis of a stage 3 or 4 primary GI (i.e., pancreatic, colorectal, hepatocellular, 
biliary, and gastro-esophageal) cancer. 
2.
Must be willing to sign the informed consent form (ICF) and follow the study procedures as 
outlined in the ICF for the duration of the study.
3.
Must be 18 years or older.
4.
Must speak English and/or Spanish.
5.
Must have a Palliative Performance Score (PPS v. 2.0) greater than or equal to 40%. 
Note: See Appendix 1.
6.
Must be able to swallow liquid oral medication.

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7.
Must self-report moderate-to-severe demoralization (DS-II≥10 per Demoralization Scale-II) that 
is stable. 
Note: Stable is defined as DS-II ≥10/32 two times ≥7 days apart.
8.
Must discontinue the following medications and refrain from taking them for the duration of study 
participation (participants who require these medications will be taken off study):
a)
Lamotrigine 
b)
Clozapine
c)
PRN (as-needed) anxiolytics
Note: Benzodiazepine use may be allowed if used in a regular, scheduled way. Consultation 
with the Principal Investigator is recommended.
d)
Dopamine agonists
e)
Lithium
9.
Female-born participants of child-bearing potential with male-born partners must use highly 
effective contraception for at least 1 month prior to ketamine administration (on day 0) and 
agree to use such a method for an additional 2 months after ketamine administration.
10. Male-born participants with female-born partners of child-bearing potential must use highly 
effective contraception for at least 1 month prior to ketamine administration and agree to use 
such a method for an additional 2 months after ketamine administration.
Note: Highly effective contraception include:

Intrauterine device (IUD) 

Intrauterine hormone-releasing system (IUS) 

Non-oral hormonal methods, including injected, intravaginal, implanted, transdermal 

Oral hormones plus a barrier contraception (condom, diaphragm, or spermicide) 

Double barrier method (at least two of the following: condom, diaphragm, and 
spermicide) 

Vasectomy 

Abstinence from penile-vaginal intercourse* 
*The reliability of abstinence should be evaluated carefully with the participant in 
relation to their general lifestyle. An additional acceptable birth control method 
should be discussed with the participant in case they decide to engage in penile-
vaginal intercourse during the course of the study.
11. Must agree to the following lifestyle considerations:
a)
Continue receiving psychotherapy or other behavioral interventions for mental health as 
usual. Current interventions should not be stopped, and new interventions should not be 
started during the study period once participants are enrolled in the study. 
b)
Consume no more than a modest quantity (e.g., 1 cup) of caffeine or xanthine-containing 
products (e.g., coffee or tea) the morning of receiving ketamine (on Day 0/Visit 4).
c)
Abstain from alcohol for 24 hours before receiving ketamine. 
d)
Abstain from using any nicotine-containing products (including nicotine patches) for 3 hours 
before receiving ketamine.
e)
If cannabis products are used regularly, participants will be asked to continue using their 
regular amount but will be asked not to use cannabis within 24 hours prior to receiving 
ketamine.
f)
If prescribed a regular dose of benzodiazepines, will be asked not to take their medication 
the morning of the ketamine administration visit.
g)
If taking any psychostimulants (e.g., methylphenidate), will be asked not to take 
psychostimulant drugs (other than caffeine) the morning of the ketamine administration visit.
h)
Will be advised to maintain their usual opioid regimen. 

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Note: Input will be obtained from the participant’s regular clinical providers on appropriate pain 
management for the participant during the study, particularly in the case of analgesics 
associated with adverse reactions of concern with ketamine (e.g., tramadol and any opioid may 
increase the risk of respiratory depression from ketamine). 
3.3.2
Exclusion Criteria
An individual who meets any of the following criteria will be excluded from participation in this study:
1.
Has a known allergic or severe reactions to the non-psychoactive components of liquid 
ketamine.
2.
Has received treatment with another investigational drug or intervention within 1 month of 
signing Informed Consent Form (ICF).
3.
If deemed by the clinical judgment of the study investigators to be unsafe for undergoing the 
intervention.
4.
Has used ketamine within 5 years of signing ICF.
Note: Ketamine used for anesthesia for medical procedures is permissible.
5.
Has a lifetime use of ketamine for non-anesthetic purposes ≥10 times.
6.
Has a history of intracerebral hemorrhage.
7.
Has cognitive impairment sufficient to impede the ability to complete study tasks.
8.
Has had delirium/encephalopathy within 3 months of signing ICF.
9.
Has a history of intracranial hemorrhage.
10. Has had a stroke (embolic) within 12 months of signing ICF.
11. Has had a seizure within 6 months of signing ICF.
12. Currently has an intracranial mass (e.g., primary tumor or brain metastasis).
13. Has an advanced stage of a neurologic disease that puts patients at elevated risk for 
psychosis (e.g., Parkinson or Huntington disease).
14. Has a history of a primary psychotic disorder or primary bipolar disorder I or II (determined by 
QuickSCID-5).
15. Has a history of dissociative disorder.
16. Has active suicidal ideation with intent in the last 2 months (Suicidal ideation score ≥4 and 
Reason for ideation >1 on C-SSRS). 
Note: This does not include requesting medical aid in dying.
17. Is currently receiving electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) 
or similar somatic therapies.
18. Has baseline hypertension (≥150 SBP or ≥90 DBP), after repeated measurements. 
Note: Participants with hypertension that has been controlled by medication down to <150 SBP 
and <90 DBP will be allowed to participate. 
19. Has a history of aneurysmal vascular disease or dissection (including thoracic and abdominal 
aorta, intracranial, and peripheral arterial vessels) or arteriovenous malformation.
20. Has had cardiac arrest within 12 months of signing ICF.
21. Has had a myocardial infarction within 12 months of signing ICF.
22. Has QTcf >480msec on 12-lead EKG.
Note: Participants may qualify for the study if QTc 480-500 msec on one EKG, but then ≤480 
msec on repeat EKG taken >1 day later. If QT-prolonging medications are started or increased 
in dose after enrollment and prior to ketamine administration, a repeat EKG must be done >12-
hours after this change in order to assure continued safe enrollment in the trial.
23. Has clinically significant arrhythmia defined as:
a)
Ventricular fibrillation or ventricular tachycardia within 1 year of signing ICF
b)
Bradycardia, severe, within 1 year of signing ICF 
Note: Participants with pacemakers will be considered to be eligible at the discretion of the 
Principal Investigator.

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c)
Atrial fibrillation, without rate or rhythm control
d)
Supraventricular tachycardia (SVT), without standard treatment
e)
Other clinically significant arrhythmias (e.g., Wolf Parkinson White)
24. Has symptomatic congestive heart failure (NYHA Class II-IV)
25. Has severe obstructive intracardiac abnormalities (e.g., aortic stenosis)
26. Has any current condition where physical activity is associated with palpitations, anginal pain or 
syncope.
27. Is unable to protect their own airway due to dysphagia, difficulty swallowing, or a neurologic 
disease resulting in a risk of aspiration. 
28. Has a history of flash pulmonary edema within 12 months of signing ICF.
29. Has a diagnosis of moderate or severe pulmonary hypertension. 
30. Needs supplemental oxygen (intermittent or continuous).
31. Has current intractable nausea/vomiting/diarrhea.
32. Meets the following laboratory parameters:
a)
Asymptomatic ALT or AST ≥5x ULN.
b)
Symptomatic ALT or AST ≥2x ULN.
c)
Total bilirubin > 2x ULN [Gilbert syndrome is allowed]
d)
Alkaline phosphatase >5x ULN
e)
INR > 2.5 for patients with any history of cirrhosis or gastrointestinal bleeding within 
6 months of signing ICF. (An INR measurement is otherwise not required). 
f)
Renal insufficiency (i.e., eGFR < 30mL/min/1.73 m2 [using the 2021 Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation], CrCl 
< 30mL/min [using the Cockcroft-Gault Equation], or current dialysis)
33. Is currently pregnant or breastfeeding.
34. Has insulin-dependent diabetes with diabetes-related hospitalization within 6 months of signing 
ICF.
3.4
Inclusion and Recruitment of Women and Minorities
3.4.1
Eligibility of Women and Minorities
Individuals of any sex/gender, race, or ethnicity are eligible for this study. 
The study recruitment strategy aims to achieve representation of minority groups that reflects the 
demographics of the affected population in the catchment area. This includes consideration of 
outreach programs to conduct or support recruitment of women and members of minority groups as 
participants and design of the clinical trial to include a valid analysis plan of whether variables being 
studied in the trial affect women or minority groups. 
3.5
Inclusion Across the Lifespan
3.5.1
Age Range of Participants
Individuals ages 18 and over are eligible for this study. Children are excluded from the study 
because insufficient data on prospective benefits and/or adverse events for a treatment that includes 
potentially fatal risks poses unacceptable risk to children.
3.5.2
Study Design/Recruitment Considerations Related to Age Groups
The study design and recruitment strategy aim to achieve representation of age groups that reflect 
the demographics of the affected population. This includes adults aged 18 or older. GI cancers occur 
at any age but mostly in patients aged 60 or older. To maximize the generalizability of results, 

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enrollment should reflect the age distribution of the affected population who is likely to use the 
investigational drug(s) in clinical practice.
3.6
Duration of Treatment
Ketamine treatment will be given on Day 0. K-MaP therapy will continue from Day -13 to Day 14 
(about 28 days) or until:

Inter-current illness that prevents further administration of treatment;

Unacceptable adverse event(s);

Participant decides to withdraw from the study;

Significant participant non-compliance with protocol;

If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation

General or specific changes in the participant’s condition render the participant unacceptable 
for further treatment in the judgment of the investigator.
3.7
Duration of Follow Up
Participants will be followed for 35 days (+/- 2 days) after treatment with ketamine (on Day 0/Visit 4) 
or removal from the study, whichever occurs first.  Participants removed from the study for 
unacceptable treatment- or study-related adverse event(s) will be followed until resolution or 
stabilization (as determined by the investigator), whichever occurs first.
3.8
Randomization Procedures
A total of 12 patients will be randomized on Day 0 at a 1:1 ratio to receive either 0.5 mg/kg of oral 
ketamine, or 0.5 mg/kg of IM ketamine. Randomization will be in block sizes of 4.
3.9
Primary Completion 
Each individual will participate for at least 7 weeks (Day 35) plus [up to 4 weeks] from telephone 
screening to the baseline study visit (between Day -28 to -7). The expected primary completion date 
for a sample of 12 participants is 1.5 years after the study opens to accrual.
3.10
Study Completion
The expected on-study completion date is 1.5 years after the study opens to accrual.
4
Investigational Products
4.1
Description, Supply and Storage of Investigational Products
4.1.1
Ketamine
Classification
NMDA-receptor antagonist 
Mechanism of Action
Ketamine is a nonselective, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. The 
mechanism by which it exerts its antidepressant effect is unknown; a transient dissociative 
experience correlates with better depression outcomes. The major circulating metabolite 
norketamine demonstrated activity at the same receptor with less affinity.

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Metabolism
Substrate of CYP2B6 (major), CYP2C19 (minor), CYP2C9 (minor), CYP3A4 (minor). Note: 
assignment of major vs. minor substrate states are based on clinically relevant drug interaction 
potential
Contraindications
Hypersensitivity to esketamine, ketamine, or any component of the formulation; aneurysmal vascular 
disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) or 
arteriovenous malformation; history of intracerebral hemorrhage
Formulation, Appearance, Packaging, and Labeling
This study will use commercially available (non-diluted) ketamine (ideally, 50mg/mL - NDC 42023-
114-10, manufactured by Par Pharmaceutical). However, if not available due to market inventory, we 
will substitute with a generic alternative or different concentration of commercially available product 
(i.e., ketamine 50mg/mL - NDC 0143-9508-10, manufactured by Hikma; ketamine 50mg/mL - NDC 
55150-439-10, manufactured by AuroMedics Pharmaceuticals; ketamine 10mg/mL - NDC 42023-
113-10, manufactured by Par Pharmaceutical; ketamine 10mg/mL - NDC 55150-438-10, 
manufactured by AuroMedics Pharmaceuticals; ketamine 100mg/mL - NDC 42023-115-10, 
manufactured by Par Pharmaceutical; ketamine 100mg/mL - NDC 0143-9509-10, manufactured by 
Hikma; or ketamine 100mg/mL - NDC - 55150-440-10, manufactured by AuroMedics 
Pharmaceuticals). Review the FDA approved package labeling for ketamine for more information.
Availability
Ketamine (Ketalar) is an FDA approved product. We will purchase it from AmerisourceBergen, a 
commercial distributor. If the Par Pharmaceutical formulation is not available, we will substitute with 
one of the other formulations available 
, as described above. 
Storage and handling
Store at 20° to 25°C (68° to 77°F). Protect from light.
Review the FDA approved package labeling for ketamine (Ketalar) for more information.
Side Effects
Complete and updated adverse event information is available in the FDA approved package labeling 
for ketamine (Ketalar).
4.2
Accountability Records for Investigational Product(s)
The Principal Investigator and research team will be responsible for managing investigational 
product accountability records, including inventory logs, transfer forms, and usage logs in 
compliance with the UCSF Controlled Substances Program Manual: 
 
After consulting with the UCSF Investigational Drug Service, it was determined that they will not be 
engaged in this trial due to the non-General Acute Care Hospital (GACH) setting of the study site.
4.3
Ordering Investigational Product
The Principal Investigator will obtain ketamine (Ketalar) directly from a commercial distributor, 
AmerisourceBergen. If not available through the commercial distributor due to inventory issues, the 
Principal Investigator has received approval from the Director of the Investigational Drug Pharmacy 

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Services at UCSF Health to obtain ketamine (Ketalar) through a transfer from the UCSF Parnassus 
Pharmacy as a DEA coincident activity for research purposes. 
5
Treatment Plan
K-MaP will consist of 4 sessions of Meaning and Purpose (MaP) therapy and a single dose of ketamine 
on day 0. Two MaP sessions will occur prior to ketamine therapy, the 1st session between days -13 
and -7, and the second session between days -12 to -1. The two sessions of MaP after ketamine 
administration will occur on days 3 (+/- 2 days) and 11 (+/- 3 days). MaP sessions may occur in-person 
at UCSF or via telehealth; however, we will strongly recommend that participants undergo at least one 
of the first two MaP sessions in-person when doing so is logistically feasible.
MaP is a manualized existential behavioral intervention, in which participants discuss their condition, 
their thoughts and feelings about their health and life, and are prompted to explore what brings 
meaning to their life. All MaP sessions and the ketamine administration visits will be video- and audio-
recorded on a camcorder with a removable storage chip or PHI-compliant software (i.e., Zoom). The 
recordings on the chips will be downloaded onto encrypted external hard drives. The camcorders, 
chips, and hard drives will be stored in locked cabinets in a secure and locked room. The recordings 
will be securely uploaded to a dedicated UCSF Research Analysis Environment (RAE) workspace for 
analysis at a later date.  Transcripts of recordings will be analyzed to assess treatment fidelity and 
qualitative assessment of the participant’s subjective experiences. MaP sessions will not be billed to 
participants or their insurance.
After two MaP sessions, participants will receive ketamine on Day 0. This session will last about 4 
hours. Participants will arrive to the Neurosciences Clinical Research Unit (NCRU) of the Sandler 
Building at UCSF Mission Bay, where they will be oriented to the treatment room for this study, which 
will contain a couch or bed for the participant to lie on in a private setting. Participants will hand over 
their shoes, keys, wallet, and phone to the study clinicians for safekeeping; these will all be returned 
to the participant upon completion of the treatment session. They will then complete all pre-
randomization assessments described in Section 6 of this study protocol. The ketamine session will 
be audio and video recorded, but participants will have the option of requesting that the recording be 
paused momentarily if they wish to discuss matters that are too personal to be recorded. There will be 
an on-site study physician (MD or DO) with 1) experience in the management of psychiatric 
emergencies and 2) experience or certification in the management of cardiovascular emergencies.  
Ketamine, its administration, and the medication visit will be paid for by the study and will not be billed 
to participants or their insurance.

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During the medication session, vital signs (heart rate and blood pressure) will be recorded at 10 
minutes prior to ingestion of the oral solution (“Minute -10”), and then 30, 60, 90, 120, and 180 minutes 
after oral ingestion. If at 180 minutes blood pressure is meaningfully elevated compared to Minute -
10, blood pressure will continue to be repeatedly assessed until it has returned to near its Minute -10 
measurement. Respiratory rate and oxygen saturation will be assessed as needed.
The participant will be randomized to ingest liquid ketamine 0.5mg/kg vs. an equivalent mL quantity 
of normal saline (placebo) mixed with cranberry juice (prepared by unblinded study staff) in a 
medication administration room located next door to the treatment room. At 10 minutes following oral 
ingestion of cranberry juice, while sitting in a wheelchair in the medication administration room, all 
participants will be administered an intramuscular injection (also prepared by unblinded study staff). 
The injection will be administered either by an RN, NP, or MD/DO involved in the study. Participants 
who received oral ketamine 0.5mg/kg will be administered normal saline via IM injection while those 
who received normal saline (placebo) in cranberry juice will receive ketamine 0.5 mg/kg IM. 
Following this injection, the participant (still in a wheelchair) will be rolled into the treatment room 
located across the hall from the medication administration room, where they will be supported by the 
therapy facilitators in transferring from the wheelchair to the couch and instructed to lie down 
wearing eyeshades and listening to a preselected music playlist via headphones or speakers. The 
participant will be instructed to focus their attention internally and to attempt to interact minimally with 
the two facilitators present in the room throughout the drug session. The facilitators will be as non-
directive as possible in their interactions with the participant. In the event of a psychologically 
challenging experience such as significant anxiety or confusion, the facilitators will provide verbal 
reassurance and, when consented to prior to the session, supportive touch (e.g., brief handholding 
or hand-on-shoulder). Participants will have been instructed in the preparatory therapy session to 
notify the study therapists if during the treatment they feel anxiety or fear.
Facilitators will work in dyads (one Lead Facilitator and one Assistant Facilitator) and have licensure 
or clinical experience according to the following requirements, which the FDA has used for prior 
studies of medication-assisted talk therapy: 
Lead Facilitator: Licensed to provide healthcare with professional training and clinical experience in 
psychotherapy. They must be licensed to practice independently. Acceptable professional credentials 
are limited to the following: clinical or counseling psychologist (PhD or PsyD), psychiatrist or other 
In the event of elevated blood pressure prior to study drug administration
If the Minute -10 assessment (the mean of at least two readings separated by at least 2 
minutes) of blood pressure exceeds either 140 systolic or 90 diastolic, periodic blood pressure 
readings will be obtained (e.g. at 5-minute intervals) to determine if the elevation may be 
temporary (e.g. due to anticipatory anxiety). If blood pressure decreases to (or below) 140 
systolic and 90 diastolic within 20 minutes, study drug administration will proceed. 
If blood pressure continues to exceed either 140 systolic or 90 diastolic, periodic blood 
pressure readings will be continued, and the study physician will be contacted. The study 
physician can authorize study drug administration if the study physician believes that it is safe 
to proceed and if the last two blood pressure readings do not exceed 155 systolic or 95 
diastolic. The determination that it is safe to proceed requires that 1) the participant endorses 
currently feeling anxiety, 2) the participant is <70 years of age, 3) the participant’s medical 
history is negative for stroke, myocardial infarction, heart failure, flash pulmonary edema. The 
study physician must regularly care for patients with serious medical illness and/or in acute 
care settings.

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physician (MD or DO), Master of Social Work (MSW), masters Licensed Clinical Professional 
Counselor (PCPC), or licensed Psychiatric Nurse Practitioner (Psychiatric NP).
Assistant Facilitator:  Must have at least a bachelor’s degree and at least one year of clinical 
experience in a licensed healthcare setting. Their clinical experience may have been in medical 
care, mental health care, or professional spiritual care (aka, chaplaincy). 
In the event of a psychiatric emergency, verbal de-escalation and physical and/or chemical restraint 
will be used to maintain the safety of the participant and the facilitators, according to the clinical 
judgment of the on-call study physician. All reasonable efforts will be made to avoid using restraints 
of any kind. Participants will not be allowed to leave the premises until the drug effects have worn off. 
In the event of a medical emergency, participants will be evaluated by the on-call study physician. At 
least one ACLS-certified study clinician will be on-site for all drug administrations. While expected to 
be rare, the most likely non-psychiatric serious adverse event to occur would be a hypertensive crisis. 
If a participant’s blood pressure becomes grossly elevated (SBP >180mmHg, DBP >110mmHG) or 
unsafe (BP elevations with associated symptoms such as chest pain or shortness of breath), blood 
pressure will be rechecked immediately in both arms and the on-call physician will be notified if s/he 
is not already in the treatment room. If the participant is clinically suspected of being in hypertensive 
emergency (with signs of end-organ damage), then the participant will be transported to the nearest 
Emergency Department for further evaluation and treatment. If the participant is determined to be in 
hypertensive urgency (without clinical signs of end-organ damage), then blood pressure will be re-
assessed with greater frequency while the study physician continues her/his evaluation for signs of 
clinical instability, and the study staff may attempt to calm the participant with verbal de-escalation, a 
short-acting blood pressure medication (e.g. clonidine), or an anxiolytic (e.g. lorazepam), as transient 
hypertension is often due to a challenging psychological experience. If after 30 minutes, the 
hypertensive urgency has not improved, the study physician will evaluate the need for transporting the 
participant to the Emergency Department for further evaluation and treatment. 
In the case of acute chest pain, the on-call study physician will have available sublingual nitroglycerin 
to administer to the participant. An automated external defibrillator (AED) will be located in the building, 
but the goal will be to transport a decompensating patient to the Emergency Department prior to an 
AED becoming necessary. 
As the drug effects begin to wear off at the 1.5-2-hour mark, the facilitators will engage the 
participant in a therapeutic interview (also video-recorded) to explore the experience. Patient-
reported outcomes characterizing the Ketamine experience—the Mystical Experience Questionnaire 
(MEQ) and the Challenging Experience Questionnaire (CEQ)—will be obtained.
Trained study staff will administer the Columbia suicidality rating scale (C-SSRS) and the Heartbeat 
Detection (HBD) task. Only once participants are deemed to be free of the acute effects of ketamine, 
and after at least 3 hours have passed since ingestion of ketamine, will the participant be allowed to 
leave the premises in the company of a caregiver who has been instructed on how best to support the 
participant over the coming days.
The participant and caregiver will be given a study clinician’s pager or work cell phone number in case 
of any clinical event off-site that needs further assessment. Participants must agree not to drive 
themselves home nor to drive later that same day after they arrive home. Participants will be instructed 
to write a detailed account of their experience as soon as possible over the following week.
Participants will be reminded well before the day of ketamine administration that a caregiver will need 
to take them to and from the 4-5-hour appointment. In the event that a participant did not arrange a 
friend/family member to accompany them home, the participant will be required to stay with the study 

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staff, will be encouraged to eat, and then the participant will be escorted outside by a study team 
member who will accompany the participant home in a taxi/Lyft/Uber. The taxi/Lyft/Uber fee will be 
paid for by the study. 
5.1
Dosage and Administration
Treatment with ketamine will be administered on an outpatient basis, on Day 0/Visit 4.
This session will last about 4-5 hours. Participants will arrive to the Neurosciences Clinical Research 
Unit (NCRU) of the Sandler Building at UCSF Mission Bay, where they will be oriented to the treatment 
room for this study, which will contain a couch or bed for the participant to lie on in a private setting. 
Participants will hand over their shoes, keys, wallet, and phone to the study clinicians for safekeeping; 
these will all be returned to the participant upon completion of the treatment session. The session will 
be audio and video recorded for subsequent behavioral analysis and rating of clinician adherence to 
the trial protocol. Participants will have the option of requesting that the recording be paused 
momentarily if they wish to discuss matters that are too personal to be recorded. There will be an on-
site study physician (MD or DO) with experience in the management of psychiatric emergencies and 
experience or certification in the management of cardiovascular emergencies.  Ketamine, its 
administration, and the medication visit will be paid for by the study and will not be billed to participants 
or their insurance. The participant will be randomized to ingest liquid ketamine vs. an equivalent mL 
quantity of normal saline (placebo) mixed with cranberry juice (prepared by unblinded study staff) and 
then be administered an intramuscular injection (prepared by unblinded study staff) 10 minutes later. 
Participants who received oral ketamine 0.5mg/kg will be administered normal saline via IM injection 
while those who received normal saline (placebo) in cranberry juice will receive ketamine 0.5 mg/kg 
IM. Following this injection, participants will be moved from the medication administration room into 
the treatment room via wheelchair, transferred to the couch, and instructed to close their eyes while 
wearing eyeshades and listening to a preselected music playlist via headphones and speakers. The 
participant will be instructed to focus their attention internally and to attempt to interact minimally with 
the two facilitators, who will be present in the room throughout the drug session but will be as non-
directive as possible in their interactions with the participant. In the event of a psychologically 
challenging experience such as significant anxiety or confusion, the facilitators will provide verbal 
reassurance and, when consented to prior to the session, supportive touch (e.g., brief handholding or 
hand-on-shoulder). Participants will have been instructed in the preparatory therapy session to notify 
the study therapists if during the treatment they feel anxiety or fear.
Ketamine preparation
On Day 0, an unblinded preparer will draw up a 0.5 mg/kg dose of liquid ketamine solution 
into a syringe. They will also draw up an equivalent mL quantity of normal saline in an identical 
syringe. Using a computer-generated randomization scheme, they will then mix either the 
liquid ketamine or normal saline solution into a cup of cranberry juice. This drug-cranberry 
juice admixture and the second syringe (containing either ketamine or saline solution) will 
then be handed to a blinded study therapist, who will administer the medications to the study 
participant.
Investigational 
Product
Premedication; 
precautions
Dose
Route
Schedule
Ketamine
N/A
0.5 mg/kg
Oral or 
Intramuscular
One dose, on 
Day 0/Visit 4

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5.1.1
Rescue Medications
The study site will have rescue medications on-site for use, as needed, during the ketamine 
administration visit. Rescue medications will be obtained locally. The following rescue medications 
may be used:

Benzodiazepine for acute, severe anxiety or agitation not relieved by verbal de-escalation. 

Lorazepam 1-2mg PO or Diazepam 5-10mg PO

Olanzapine for acute, severe psychosis or agitation not relieved by verbal de-escalation.

Zyprexa Zydis (olanzapine) 5-10mg SL

Olanzapine 10mg vial (5mg/mL) IM

Clonidine for hypertensive urgency not thought to be associated with anxiety. 

Clonidine 0.1-0.2mg PO

Nitrogylcerin for acute angina pectoris.

Nitroglycerin 0.4mg SL 

Ondansetron for nausea or vomiting and/or as pre-treatment 30-60 minutes prior to ketamine 
dosing for participants who report being prone to medication-induced nausea or who regularly 
experience nausea associated with pre-existing medical conditions. 

Ondansetron 4-8mg SL 
Although the use of rescue medications is allowable to protect the safety and well-being of study 
participants and staff during the ketamine administration visit, the use of rescue medications is not 
expected to be necessary in this study. If used, the date and time of rescue medication administration 
as well as the name and dosage of the rescue medication must be recorded. 
6
Study Procedures and Schedule of Events
Assessment Plan
Patient-reported outcomes of demoralization (DS-II), depression (PHQ-9), anxiety (GAD-7), Quality 
of Life (FACIT-Pal-14), pain (BPI-SF), and opioid use (<24hr morphine milligram equivalence (MME), 
will be obtained at baseline, immediately prior to randomization (on Day 0), and post-ketamine at 
follow-up assessments on days 7, 14, and 35. In addition, a patient-reported outcome of 
interoceptive awareness (MAIA-2) will be obtained once immediately prior to randomization (on Day 
0) and post-ketamine at follow-up assessment on Day 7. 
As an objective measure of cardiac interoceptive accuracy, an 8-minute heartbeat detection (HBD) 
task will be conducted with participants while measuring their peripheral physiology using 
electrocardiography (ECG), respiratory rate (RR) and skin conductance (SC) monitoring, twice on 
Day 0—once at least 15 minutes prior to dosing of the oral solution and a second time at least 3 
hours following dosing of the oral solution. 
Patient-reported outcomes characterizing the Ketamine experience—the Mystical Experience 
Questionnaire (MEQ) and the Challenging Experience Questionnaire (CEQ)—will be obtained on Day 
0 after the medication effects have worn off (about 1.5-2 hours after Ketamine administration).

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Clinician-rated outcomes of global clinical impression of severity (CGI-S), demoralization (DI), and 
mood symptoms (GRID-HAMD-6) will be assessed at baseline, immediately prior to randomization, 
and post-ketamine administration on days 14 and 35. 
As a safety measure, the Columbia suicidality rating scale (CSSRS) will be given at every study visit 
(Visits 1-9, starting on Day -28 to Day 35). Trained study staff will assess the participant for onset or 
exacerbation of suicidal idealization or behavior. If at any time the participant is unwilling to continue 
the study, they will be allowed to stop (except while under the acute effects of study drug ketamine on 
Day 0/Visit 2). Support services from therapists and clinicians will be available to the participant at 
each study visit. The participant will continue receiving their regular medical care, separate from this 
study.
Patient-reported measures include:

Demoralization Scale-II (DS-II): A well-validated self-report measure of demoralization [4]. This 
16-item, 3-point scale has a 2-week recall period and produces a total score than can range 
0-32, with higher scores indicating a greater degree of demoralization. It has also been 
validated for use with Spanish-speaking patients from both Spain and Latin America [5]. 

Patient Health Questionnaire-9 (PHQ-9): A validated and widely-used 9-item, 4-point scale (0 
= “Not at all” to 3 = “Nearly every day”) that assesses depression symptom severity with a 2-
week recall period [74]. Higher scores indicate worse depression. The scale has also been 
validated in Spanish [75].

General Anxiety Disorder-7 (GAD-7): A validated self-report measure for the severity of 
generalized anxiety disorder (GAD) symptoms. This 7-item, 4-point scale (0 = “Not at all” to “3 
= Nearly every day”) scale has 2-week recall period. Item scores are summed to produce a 
total score that can range 0-21, with higher scores indicating greater severity of symptoms of 
GAD [76]. The measure has been validated in Spanish [77].

Functional Assessment of Chronic Illness Therapy Palliative Care 14 Item Version (FACIT-
Pal-14): A validated 14-item, self-report measure of quality of life in palliative care patients. 
The measure has a 7-day recall period and consists of 14-items with a 5-point Likert scale (0 
= “Not at all” to 4 = “Very much”) [78]. The measure has good internal consistency with a single 
underlying latent variable [79], and has been validated for use with Spanish-speaking patients 
with advanced cancer [80].

Brief Pain Inventory-Short Form (BPI-SF): A validated and widely-used self-report measure of 
pain over the last 24-hours in patients with and without cancer [81, 82]. This 15-item measure 
consists of a 4-item, 11-point subscale measuring pain intensity (Severity); a 7-item 10-point 
subscale measuring impact on functioning and well-being (Interference); 2 open-ended 
questions measuring location of pain and type of pain treatment used; and a single-item 11-
point subscale measuring the effectiveness of treatment. The BPI-SF Spanish version has 
been validated for use with patients from Spain with cancer-related [83] and non-cancer-
related pain [84].

Morphine Milligram Equivalents (MME): Calculates the patient’s cumulative daily dose of 
opioids.

Multidimensional Assessment of Interoceptive Awareness, Version 2 (MAIA-2): A validated a 
widely used questionnaire to measure interoceptive awareness [85]. This measure consists 
of 37-items using a 6-point Likert scale (0 = “Never” to 5 = “Always”). It has demonstrated 
good internal consistency and reliability for the evaluation of clinical mind-body interventions, 
with higher scores indicating increased. 

Heartbeat Detection (HBD) Task: Participant’s bodily physiology will be measured with a 
respiration belt, galvanic skin conductance (SC) sensors, and EKG sensors while they perform 
an 8-minute heart beating detection task. During the first two 2-minute blocks of this task, they 
will be instructed to press a button on a keyboard each time they hear a heartbeat on the 

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speaker. During the last two 2-miute blocks of this task, they will be instructed to press a button 
on a keyboard each time they think they are having a heartbeat. The physiological sensors 
are non-invasive and cause minimal discomfort. This task has been validated as a novel index 
of cardiac interoceptive accuracy [86, 87]. 

Mystical Experience Questionnaire (MEQ): A validated self-report, 30-item, 6-point scale of 
mystical-type experiences, derived from surveys of subjective responses to psilocybin [88, 89]. 
Participants are asked to “please rate the degree to which at any time during that [medication] 
session you experienced the following phenomena;” each item is rated from 0 = “none; not at 
all” to 5 = “extreme (more than any other time in my life and stronger than 4)”. The total score 
is calculated by the sum of all items. A higher score indicates a more mystical-type experience 
[90].

Challenging Experience Questionnaire (CEQ): A validated 26-item self-report measure of 
challenging experiences with psychedelics, the CEQ assesses seven factors: grief (5 items), 
fear (6 items), subjective experience of death (2 items), insanity (3 items), isolation (3 items), 
physical distress (5 items), and paranoia (2 items). Each of the 26 items is scored on a 5-point 
Likert scale (0 = “None; not at all” to 5 = “Extreme [more than ever before in my life]”), with 
participants asked to “please rate the degree to which at any time during that [medication] 
session you experienced the following phenomena.” A higher total CEQ score indicates 
greater psychologically adverse reactions to psilocybin [91].
Participants may complete these measures on an electronic tablet (using a REDCap survey) or by 
paper and pencil, whichever is their preference. In the event the participant opts for a telehealth visit, 
the study team may email the participant a link to the REDCap survey. Some visits must be in-person 
(see Study Calendar in Section 6.1 for more details).
Clinician-rated outcomes include:

The Clinical Global Impressions Scale (CGI): The CGI is a widely-used 3-item clinician-
administered measure developed by the NIMH to assess clinical change in patients in 
psychopharmacology trials [92]. The scale has previously been modified to detect clinical 
change in specific populations [93, 94]. In this trial we use the Global Impression of Severity 
item (“Considering your total clinical experience with patients with demoralization, how would 
you rate this participant’s level of demoralization at this time?”), on the scale from “1 = Normal, 
not at all demoralized” to “7 = Among the most extremely demoralized patients” to assess 
specifically for change in demoralization as a secondary endpoint.

Demoralization Interview (DI): A clinician-administered, 14-item structured interview designed 
from items of the Demoralization Scale-II [95, 96]. The DI has demonstrated good reliability 
and validity, with a threshold of 6 symptoms supporting a diagnosis of demoralization. 

GRID Hamilton Depression Rating Scale 6 (GRID-HAMD-6): The 6-item Hamilton Depression 
Rating Scale (HAMD-6) is a validated, brief, clinician-rated measure of the core symptoms of 
major depression [97, 98]. The measure is highly sensitive to change in pharmacotherapy 
trials. The GRID version of the Hamilton Depression scale is a structured and highly reliable 
version of the classic Hamilton Depression scale [99-101]. With permission from the owner of 
the GRID-HAMD, the International Society for CNS Drug Development, we will use the 6-items 
of the HAMD-6 in the GRID-HAMD format to create a brief, responsive and reliable measure 
of core depression symptoms for this trial.

Columbia Suicidality Severity Rating Scale (C-SSRS): A validated 17-item scale that assesses 
suicidal ideation and behavior according to the Columbia Classification Algorithm for Suicide 
Assessment (C-CASA) [102]. The C-SSRS is made up of ten categories, consisting of binary 
responses (yes/no), to indicate presence or absence of suicidal ideation or behavior (e.g., 
Wish to be Dead or Aborted Attempt). A numerical score for the C-SSRS is obtained from the 
aforementioned categories. A validated version of the C-SSRS exists in Spanish [103].

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The clinician may complete their assessment in-person or over video conference/phone if the 
participant opts for a telehealth visit.
On Day 35, the last visit day, participants will be interviewed on the acceptability and tolerability of K-
MaP. This interview will be audio-recorded and conducted with study staff, either via 
phone/teleconference or in-person, depending on participant preference. 
The study-specific procedures and assessments are detailed in this section and outlined in the Study 
Calendar – Section 6.1.  

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6.1
Study Calendar
≥7, ≤28 days 
before 
Enrollment
Day -28 to -7
Day -13 to -4
Day -12 to -1
Day 0
Day 3 +/- 2 days
Day 7 +/- 2 days
Day 11 +/- 2 days
Day 14 +/-2 days
Day 35 +/- 2 days
 
Phone Screening 
V1   [Enrollment/ 
Baseline]
V2 
[MaP Session 1]
V3
[MaP Session 2] 
V4  
[Randomization/
Ketamine]
V5 
[MaP Session 3]
V6 
V7
[MaP Session 4]
V8 
V9 
Verbal Waiver of Consent; Phone Screen
x
Informed Consent Form
x
 
 
 
 
 
 
 
 
Brief Clinical Interview1
x
x
Interview on Acceptability and Tolerability
x
Demographics
x
 
 
 
 
 
 
 
 
C-SSRS
 
x
x
x
x
x
x
x
x
x
Physical exam
 
x
 
 
 
 
 
 
 
Vitals (BP, HR)2
x
x
1 Partcipants will be briefly interviewed by the study team at baseline. The baseline interview will asses for clinical fit for K-MaP by evaluating participant expectations and prior experiences of altered states of consciousness . On Day 0/Visit 4, 
around 1.5-2 hours after ketamine administration (when the drug effects wear off), the facilitators will engage the participant in a therapeutic interview to explore the experience they had. The Day 0/Visit 4 interview will be video and audio 
recorded.
2 Vitals will be taken at baseline, and prior to ketamine administration on Day 0/Visit 4. On Day 0, vital signs (heart rate and blood pressure) will be recorded at 10 minutes prior to drug ingestion (“Minute -10”), and then 30, 60, 90, 120, and 180 
minutes after drug ingestion. If at 180 minutes blood pressure is meaningfully elevated compared to Minute -10, blood pressure will continue to be repeatedly assessed until it has returned to near its Minute -10 measurement. Respiratory rate 
and oxygen saturation will be assessed as needed.

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≥7, ≤28 days 
before 
Enrollment
Day -28 to -7
Day -13 to -4
Day -12 to -1
Day 0
Day 3 +/- 2 days
Day 7 +/- 2 days
Day 11 +/- 2 days
Day 14 +/-2 days
Day 35 +/- 2 days
 
Phone Screening 
V1   [Enrollment/ 
Baseline]
V2 
[MaP Session 1]
V3
[MaP Session 2] 
V4  
[Randomization/
Ketamine]
V5 
[MaP Session 3]
V6 
V7
[MaP Session 4]
V8 
V9 
Height and Weight
x
Medical/Psychiatric Hx
 
x
 
 
 
 
 
 
 
 
PPSv2
 
x
 
 
 
 
 
 
 
 
Eligibility Verification
 
x
 
 
 
 
 
 
Randomization
 
 
 
 x
 
 
 
 
 
LFTs, Creatinine, Electrolytes, PT/INR3
 
x
 
 
 
 
 
 
 
12-lead EKG4
x
DS-II5
x
x
 
 
x
 
x
 
x
x
3 The following laboratory tests are required at baseline:

Electrolytes: Sodium, potassium, carbon dioxide, and chloride. 

Liver function tests: Total bilirubin, ALT, AST, and alkaline phosphatase. 

Cogulation tests: PT/INR (for patients with a history of cirrhosis or GI bleed within past 6 months)

Renal function: Creatinine.
4 EKG is required at baseline. 
5 DS-II will be measured two times before enrollment. Once over the phone after verbal waiver of consent, and tagain, ≥7 days apart, after the participant has signed the informed consent form and started screening procedures. DS-II will also be 
measured at Visits 4 (before Ketamine administration), 6, 8, and 9. 

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≥7, ≤28 days 
before 
Enrollment
Day -28 to -7
Day -13 to -4
Day -12 to -1
Day 0
Day 3 +/- 2 days
Day 7 +/- 2 days
Day 11 +/- 2 days
Day 14 +/-2 days
Day 35 +/- 2 days
 
Phone Screening 
V1   [Enrollment/ 
Baseline]
V2 
[MaP Session 1]
V3
[MaP Session 2] 
V4  
[Randomization/
Ketamine]
V5 
[MaP Session 3]
V6 
V7
[MaP Session 4]
V8 
V9 
PHQ9, GAD7, BPI-SF, <24hr MME, 
x
x
x
x
x
MAIA-2
x
x
FACIT-Pal14
x
 
 
x
 
x
 
x
x
CGI-S, DI, GRID-HAMD6
x
x
x
MEQ, CEQ
x
MaP Therapy Session6
 
 
x
x
 
x
 
x
 
 
Ketamine therapy (day of administration)7
 
 
 
 
x
 
 
 
 
 
HBD Task8
x
6 It will be recommended that att least one MaP session prior to Day 0/Visit 4 occur in-person (i.e., MaP sessions on Visit 2 or 3)..
7 The ketamine administration visit will last approximately 4-5 hours. Patients will leave the premises once they are deemed to be free of the acute effects of ketamine, at least 3 hours have passed since ingestion of the oral drug-cranberry juice 
solution, and the study team confirms they are in the presence of a caregiver. In the event that a participant did not arrange a caregiver to accompany them home, the participant will be required to stay with the study staff and will be escorted 
outside by a study team member who will accompany them home in a taxi, Lyft, or Uber. 
8 The Heartbeat Detection (HBD) task will be administered by a trained provider twice on the day of ketamine dosing. The tasks takes about 8 minutes to complete and will administered once a least 15 minutes prior to receipt of the oral drug-
cranberry juice solution and again at least 3 hours after receipt of this oral solution.

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≥7, ≤28 days 
before 
Enrollment
Day -28 to -7
Day -13 to -4
Day -12 to -1
Day 0
Day 3 +/- 2 days
Day 7 +/- 2 days
Day 11 +/- 2 days
Day 14 +/-2 days
Day 35 +/- 2 days
 
Phone Screening 
V1   [Enrollment/ 
Baseline]
V2 
[MaP Session 1]
V3
[MaP Session 2] 
V4  
[Randomization/
Ketamine]
V5 
[MaP Session 3]
V6 
V7
[MaP Session 4]
V8 
V9 
Concomitant Meds.
 
x 
x
x
x
x
x
x
x
x
Adverse Events
 
x
x
x
x
x
x
x
x

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7
Participant Registration
A verbal waiver of consent will be obtained to collect only information essential for the screening call 
that will be conducted by phone or teleconference.
At the Enrollment study visit (Visit 1), a written, signed, informed consent form (ICF) and a Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be obtained before any 
study-specific assessments are initiated.  A copy of the signed ICF will be given to the subject and a 
copy will be filed in the medical record.  The original will be kept on file with the study records.  
All participants consented to the study will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system is password 
protected and meets HIPAA requirements.
7.1
Use of Concomitant Medications
The use of the medications listed below are not exclusionary in and of itself; rather their use will be 
evaluated by the Principal Investigator, treating physician, and/or a pharmacist on a case-by-case 
basis.

Participants receiving chemotherapy or immunotherapy should be receiving a regimen that will 
allow them to schedule their Ketamine session (Day 0/Visit 4) at least 5-7 days after the end 
of a treatment cycle and at least 5-7 days before the beginning of the next treatment cycle.

NMDA receptor antagonists (e.g., memantine, amantadine, dextromethorphan, methadone)

Chronic benzodiazepine use can be continued as a stable, scheduled regimen, except for the 
morning of the ketamine administration visit (Day 0/Visit 4)

Chronic antidepressant and serotonergic supplement use can be continued as a stable, 
scheduled regimen

Drugs that may increase the risk of hypertension and tachycardia (e.g., levothyroxine, 
monoamine oxidase inhibitors [MAOIs]) [104, 105]

Drugs that may increase the risk of seizures (e.g., metrizamide, theophylline and bupropion) 

Drugs that may increase the risk of neuromuscular blockade (e.g., atracurium and 
tubocurarine)

Inhibitors or inducers of CYP 2B6, 2C9, 3A4 (e.g., clopidogrel and ticlopidine)**
**Cytochrome P450 Inhibitors and Inducers
After careful consideration, participants may qualify for the trial if they are taking medications 
that are inhibitors or inducers of CYP 2B6, 2C9, or 3A4. Drug-drug interactions will be assessed 
against the evidence for the strength of the interaction using peer-reviewed literature (e.g., 
Flockhart Table https://drug-interactions.medicine.iu.edu/MainTable.aspx), and the participant’s 
medical status, co-morbidities, and concomitant medications will be taken into consideration.  
7.2
Dietary Restrictions
Participants will be asked to adhere to the following guidelines before receiving their 
ketamine dose (on Day 0/Visit 4):

Consume no more than a modest quantity (e.g., 1 cup) of caffeine or xanthine-
containing products (e.g., coffee or tea)

Abstain from nicotine for at least 3 hours before ketamine administration

Abstain from alcohol and any other non-prescribed substances for 24 hours before 
receiving ketamine 

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
If cannabis products are used regularly, participants will be asked to maintain their 
regular amount but will be asked not to use cannabis within 24 hours prior to 
receiving ketamine.
7.3
Prohibited Medications
The medications below may not be used during the study. If participants require these medications, 
they will be taken off-study (except for when anxiolytics as rescue medications ar used during the 
ketamine medication visit on Day 0/Visit 4).

Anxiolytics, as needed

Lithium
7.4
Evaluation of Safety
The safety parameters for this study include all laboratory tests, physical findings, and spontaneous 
reports of adverse events reported to the investigator by participants.
Safety will be assessed according to the NCI CTCAE version 5.0. 
Safety analyses will be performed for all participants who receive ketamine treatment in the trial 
(V2).
8
Safety Parameters
8.1
Definitions
8.1.1
Adverse Event (AE)
Adverse event means any untoward medical occurrence associated with the use of an intervention 
in humans, whether or not considered intervention-related (21 CFR 312.32 (a)).
8.1.2
Serious Adverse Event (SAE)
An adverse event is considered serious if, in the view of either the investigator or Sponsor-
Investigator, it results in any of the following outcomes: 

Death

Life-threatening adverse event
o
An adverse event is considered life-threatening if, in the view of either the 
investigator or Sponsor-Investigator, its occurrence places the participant at 
immediate risk of death. It does not include an adverse event that, had it 
occurred in a more severe form, might have caused death.

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function

Congenital anomaly/birth defect

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Important medical events that may not result in death, are life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the participant and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse.
8.1.3
Unanticipated Problem (UP)
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the following 
criteria:
1)
unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied;
2)
related or possibly related to participation in the research; and 
3)
suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) related to the research 
than was previously known or recognized.
Only a small subset of adverse events occurring in human subjects participating in research will 
meet these three criteria for an unanticipated problem. Furthermore, there are other types of 
incidents, experiences, and outcomes that occur during the conduct of human subjects research that 
represent unanticipated problems but are not considered adverse events. For example, some 
unanticipated problems involve social or economic harm instead of the physical or psychological 
harm associated with adverse events. In other cases, unanticipated problems place subjects or 
others at increased risk of harm, but no harm occurs.
8.2
Classification of Adverse Events
8.2.1
Severity
Adverse events are graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0.
8.2.2
Attribution 
Following expert guidance in adverse event assessment [106] and reporting [107], all serious 
adverse events (SAEs) must have their relationship to study intervention assessed by the clinician 
who examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. However, relatedness to study intervention will not be assessed for non-serious adverse 
events (AEs). The degree of certainty about causality for SAEs will be graded using the categories 
below. In a clinical trial, the study product must always be suspect. 

Related – The SAE is known to occur with the study intervention, there is a reasonable 
possibility that the study intervention caused the SAE, or there is a temporal relationship 
between the study intervention and event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study intervention and the SAE. In 
summary, the SAE is more likely related to the study intervention than to other causes.

Unrelated – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 

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intervention and event onset, or an alternate etiology has been established. In summary, the 
SAE is more likely related to other causes than to the study intervention.

Unknown – It is equally likely that the SAE is related to the study intervention as to other 
causes.
8.2.3
Expectedness
An adverse event is considered unexpected if the nature, severity, or frequency of the event is not 
listed in the study protocol, product inserts, investigator brochure or informed consent document.
8.3
Recording of Adverse Events
Refer to the Data Safety Monitoring Plan, located in Appendix 2.
8.4
Expedited Reporting 
8.4.1
Reporting to the HDFCCC Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) or to 
a study procedure, the UCSF PI or his/her designee must notify the DSMC Chair (or qualified 
alternate) within 1 business day of knowledge of the event. The contact may be by phone or e-mail.
8.4.2
Reporting to Institutional Review Board
The UCSF PI must report events to the IRB according to institutional guidelines.
8.4.3
Expedited Reporting to the FDA
If the study is being conducted under an IND, the Sponsor (or the Sponsor-Investigator) is 
responsible for determining whether or not the suspected adverse reaction meets the criteria for 
expedited reporting in accordance with federal regulations (21 CFR §312.32). 
The Sponsor (or Sponsor-Investigator) must report in an IND safety report any suspected adverse 
reaction that is both serious and unexpected. The Sponsor needs to ensure that the event meets all 
three definitions: 

Suspected adverse reaction 

Unexpected 

Serious 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report.
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after the 
Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no later 
than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report will be 
submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the information is 
available (21 CFR 312.32(d)(2)). 

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8.5
Follow-up of Adverse Events
All participants who experience adverse events will be followed with appropriate medical 
management until resolved or stabilized, as determined by the investigator. For selected adverse 
events for which administration of the study drug/intervention was stopped, a re-challenge of the 
subject with the study drug/intervention may be conducted if considered both safe and ethical by the 
investigator.
8.6
Adverse Events Monitoring
Refer to the Data Safety Monitoring Plan, located in Appendix 2.
9
Statistical Considerations and Evaluation of Results
9.1
Sample Size Considerations
9.1.1
Sample Size and Power Estimate
No formal power analysis was conducted, and no formal tests of efficacy will be conducted. This 
N=12 pilot study has a sample size sufficient for assessing the feasibility and preliminary safety of a 
novel behavioral-pharmaceutical intervention, at two different dose levels and routes of 
administration of the study drug. 
If the 0.5mg/kg PO dose of ketamine is well-tolerated (i.e., zero treatment-related SAEs) and 
demonstrates mean clinical improvement in demoralization assessed by DS-II that endures beyond 
7 days post-drug, then this would suggest a fully powered study is warranted using the 0.5mg/kg PO 
dose.
If the 0.5mg/kg IM dose of ketamine is well-tolerated (i.e., zero treatment-related SAEs) and 
demonstrates mean clinical improvement in demoralization assessed by DS-II that endures beyond 
7 days post-drug, then this would suggest a fully powered study is warranted using the 0.5mg/kg IM 
dose. 
If the either dose is well-tolerated and fails to demonstrate mean clinical improvement in 
demoralization assessed by DS-II that endures beyond 7 days post-drug, then this would suggest 
that the dose is an appropriate control for other psychoactive investigational drugs whose clinical 
effects are expected to have greater durability.
9.1.2
Randomization
Participants will be randomized 1:1, without stratification, in block sizes of 4.
9.1.3
Accrual Estimates
We estimate an enrollment rate of 1-2 participants per month, for an enrollment period lasting 6 
months. It is expected that approximately 50% of patients being referred to the study will meet 
eligibility criteria at the time of screening. The study team thus aims to screen approximately 24 or 
more potential participants.

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9.2
Analyses Plans
9.2.1
Population for Analysis
Descriptive analyses will be prepared based on the Modified Intention-to-Treat study populations, 
including all participants who received a dose of either oral or intramuscular ketamine on Day 0 (at 
0.5 mg/kg).
9.2.2
Primary Analysis (or Analysis of Primary Endpoints)
The primary objective of this pilot study is to assess the feasibility and preliminary safety of 
administering Meaning and Purpose therapy combined with oral vs. intramuscular ketamine (K-MaP) 
in demoralized patients with stage 3 or 4 GI cancers (i.e., pancreatic, colorectal, hepatocellular, 
biliary, or gastro-esophageal). Pre-determined criteria for success of feasibility include: 

A recruitment rate of 50% among referred/screened participants and those ultimately found 
to be fully eligible and enrolled in the study. 

Completion rates of (i) 75% for participation in 4 Meaning and Purpose therapy sessions and 
(ii) 80% of 5 on-study DS-II assessments (Visits 1, 4, 6, 8, and 9), in addition to receipt of 
ketamine. 

Qualitative assessment of clinician fidelity to manualized K-MaP intervention. 

Qualitative assessment of acceptability of the intervention and assessments by participants 
at the end of the study, with at least 60% of included participants completing this 
assessment. 
9.2.3
Secondary Analysis (or Analysis of Secondary Endpoints)
Secondary Objective #1: To characterize the preliminary safety and tolerability of K-MaP in 
patients with stage 3 or 4 GI cancers (i.e., pancreatic, colorectal, hepatocellular, biliary, or 
gastro-esophageal), we will analyze: 

Rates and types of adverse events (AEs), unexpected AEs, and serious AEs will be 
summarized by arm. Pre-determined criteria for assessment of tolerability to K-MaP include 
zero treatment-related serious adverse events. 

Across each study arm, changes in individual participant and mean heart rate (HR), systolic 
(SBP) and diastolic blood pressure (SBP) measurements from 10 minutes prior to ingestion 
of the oral solution to 30, 60, 90, 120, and 180 minutes post-oral ingestion, using random 
effects models that account for correlated outcomes within participants. The below 
thresholds will be used as indications of potential concern for patient safety. These estimates 
have been determined on the basis of established human safety thresholds and findings 
from a recent meta-analysis of hemodynamic responses to sub-anesthetic ketamine doses in 
patients with psychiatric conditions.[109]
o
An increase in HR baseline of greater than 25 BPM in any patient  
o
An increase in SBP of greater than 40 mm Hg in any patient 
o
An increase in DBP of greater than 25 mm Hg in any patient  

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
Mean CEQ scores on the day of ketamine administration will be compared between the two 
study arms using ANCOVA models, discussed in the next objective.  
Secondary Objective #2: To assess the magnitude and durability of improvement from 
randomization in psychosocial distress associated with K-MaP, we will measure mean trends in 
patient-reported outcomes (DS-II, PHQ9, GAD7, FACIT-PAL-14 scores) in each study arm from 
baseline visit (Day -28 to -7) to post-ketamine (on Days 7, 14, and 35). In addition, we will 
calculate the proportion of participants per arm who no longer meet criteria for moderate-to-
severe demoralization (i.e., DS-II > 10) post-ketamine. We will also measure mean trends in 
clinician-rated outcomes (CGI-S, DI, and GRID-HAMD-6 scores) per arm as above. ANCOVA 
models of follow-up endpoints as a function of study arm, adjusted for endpoints at baseline and 
randomization, will be conducted [110]. ANCOVA results will be presented graphically via mean 
trends per arm overlaid on individual trends, and via the mean (95% CI) difference between arms 
at Day 35. Cohen’s d will be calculated at each follow-up time to estimate effect sizes. Any 
missing data will be estimated through the use of single imputation with baseline observations 
carried forward.
Secondary Objective #3: We will evaluate BPI-SF scores analogously to DS-II scores. 
Secondary Objective #4: We will evaluate opioid analgesia use analogously to DS-II scores.  
Secondary Objective #5: We will be using pair t-tests to measure mean changes in MAIA-2 scores 
in each study arm from prior to ketamine administration (on Day 0) to post-ketamine (on Day 7). 
Secondary Objective #6: To assess how participants’ subjective experiences with ketamine may be 
related to clinical outcomes, subjective reports of each participant’s ketamine experience 
(videorecorded from Day 0) will be transcribed, inductively coded, and qualitatively analyzed to 
identify phenomenological content. In addition, participant MEQ and CEQ scores, which provide 
summary measures of the intensity of ketamine’s acute effects, will be evaluated for potential 
correlation with trends in DS-II, BPI-SF, and opioid use.  
Secondary Objective #7: To assess how participants’ changes in measures of cardiac interoceptive 
accuracy may be related to subjective experiences with ketamine, we will assess for correlations 
between changes in scores on the Heartbeat Detection (HBD) task following the receipt of 
ketamine (measured pre- and post-dosing on Day 0) and MEQ scores (measured post-dosing on 
Day 0). We will also evaluate for potential correlation of changes in HBD task scores following 
receipt of ketamine with post-intervention trends in MAIA-2, DS-II, BPI-SF, and opioid use.
9.3
Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable 
regulatory requirements.
Before initiating this trial, the PI will have written and dated approval from the Institutional Review 
Board for the protocol, written informed consent form, subject recruitment materials, and any other 
written information to be provided to participants before any protocol-related procedures are 
performed on any participants.  
The PI must comply with the applicable regulations in Title 21 of the Code of Federal Regulations 
(21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory requirements.  The 
IRB must comply with the regulations in 21 CFR §56 and applicable regulatory requirements.

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The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed, or the FDA has determined that the 
study is exempt from IND requirements. 
9.4
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant-facing materials 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and approved 
by the IRB of record.  Prior to obtaining IRB approval, the protocol must be approved by the Helen 
Diller Family Comprehensive Cancer Center Site Committee and by the Protocol Review and 
Monitoring Committee (PRMC).  The initial protocol and all protocol amendments must be approved 
by the IRB prior to implementation.  
9.5
Informed Consent
All participants must be provided a consent form describing the study with sufficient information for 
each participant to make an informed decision regarding their participation.  Participants must sign 
the IRB -approved informed consent form prior to participation in any study-specific procedure.  The 
participant must receive a copy of the signed and dated consent document.  The original signed 
copy of the consent document must be retained in the medical record or research file. 
9.6
Changes in the Protocol
Once the protocol has been approved by the IRB, any changes to the protocol must be documented 
in the form of an amendment.  The amendment must be signed by the PI and approved by PRMC 
and the IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to participants, an 
amendment may be implemented prior to IRB approval.  In this circumstance, however, the PI must 
then notify the IRB according to institutional requirements. 
9.7
Handling and Documentation of Clinical Supplies
The PI will maintain complete records showing the receipt, dispensation, return, or other disposition 
of all investigational drugs at the site. The date, quantity and batch or code number of the drug, and 
the identification of participants to whom the investigational product has been dispensed by 
participant number and initials will be included.  
The PI shall not make the investigational drug available to any individuals other than to qualified 
study participants.  Furthermore, the PI will not allow the investigational product to be used in any 
manner other than that specified in this protocol.
9.8
Case Report Forms (CRFs)
The PI and/or designee will prepare and maintain adequate and accurate participant case histories 
with observations and data pertinent to the study.  Study-specific Case Report Forms (CRFs) will 
document safety and treatment outcomes for safety monitoring and data analysis.  All study data will 
be entered into OnCore® via standardized CRFs in accordance with the CTMS study calendar, using 
single data entry with a secure access account.  Study personnel will complete the CRFs; the PI will 
review and approve the completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source documents.  
Source documents will be found in the participant’s medical records maintained by study personnel. 
All source documentation should be kept in separate research files for each participant. 

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In accordance with federal regulations, the PI is responsible for the accuracy and authenticity of all 
clinical and laboratory data entered onto CRFs.  The PI will approve all completed CRFs to attest 
that the information contained on the CRFs is true and accurate. 
The PI will be responsible for ensuring the accurate capture of study data.  At study completion, 
when the CRFs have been declared to be complete and accurate, the database will be locked.  Any 
changes to the data entered into the CRFs after that time can only be made by joint written 
agreement among the PI and the trial statistician.
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies. 
9.9
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring/auditing 
entity for this study.  The UCSF DSMC will monitor or audit the study in accordance with the NCI-
approved Data and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all adverse 
events and serious adverse events (SAEs). The DSMC will review study-related activities to ensure 
that the study is conducted in accordance with the protocol, local standard operating procedures, 
FDA regulations, and Good Clinical Practice (GCP).  Significant results of the DSMC 
monitoring/auditing review will be communicated to the IRB and the appropriate regulatory 
authorities at the time of continuing review, or in an expedited fashion, as applicable.  See Appendix 
2 - Data and Safety Monitoring Plan.
9.10
Record Keeping and Record Retention
The PI is required to maintain adequate records of the disposition of the drug, including dates, 
quantity, and use by subjects, as well as written records of the disposition of the drug when the study 
ends.  
The PI is required to prepare and maintain adequate and accurate case histories that record all 
observations and other data pertinent to the investigation on each individual administered the 
investigational drug or employed as a control in the investigation. Case histories include the case 
report forms and supporting data including, for example, signed and dated consent forms and 
medical records including, for example, progress notes of the physician, the individual's hospital 
chart(s), and the nurses' notes. The case history for each individual shall document that informed 
consent was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed participant consent forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study.
In accordance with FDA regulations, the PI shall retain records for a period of 2 years following the 
date a marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for such indication 
until 2 years after the investigation is discontinued and FDA is notified.

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9.11
Publications
The preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement among the Sponsor-Investigator 
and collaborators.  

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Appendix 1
Palliative Performance Scale v. 2 (PPSv2)[111]
PPS 
Level
Ambulation
Activity & Evidence of Disease
Self-Care
Intake
Conscious Level
100%
Full
Normal activity & work
No evidence of disease
Full
Normal
Full
90%
Full
Normal activity & work
Some evidence of disease
Full
Normal
Full
80%
Full
Normal activity with Effort
Some evidence of disease
Full
Normal or 
reduced
Full
70%
Reduced
Unable Normal Job/Work
Significant disease
Full
Normal or 
reduced
Full
60%
Reduced
Unable hobby/housework
Significant disease
Occasional assistance 
necessary
Normal or 
reduced
Full or Confusion
50%
Mainly 
Sit/Lie
Unable to do any work
Extensive disease
Considerable 
assistance required
Normal or 
reduced
Full or Confusion
40%
Mainly in 
Bed
Unable to do most activity
Extensive disease
Mainly assistance
Normal or 
reduced
Full or Drowsy +/- 
Confusion
30%
Totally Bed 
Bound
Unable to do any activity
Extensive disease
Total Care
Normal or 
reduced
Full or Drowsy +/- 
Confusion
20%
Totally Bed 
Bound
Unable to do any activity
Extensive disease
Total Care
Minimal to sips
Full or Drowsy +/- 
Confusion
10%
Totally Bed 
Bound
Unable to do any activity
Extensive disease
Total Care
Mouth care only
Drowsy or Coma 
+/- Confusion
0%
Death

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Appendix 2
Data and Safety Monitoring Plan 
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 
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.   
The DSMC DSA will audit up to a maximum of five cycles of treatment for each 
participant selected for the annual audit.  A total of twenty percent of the participants 
enrolled in the study will be reviewed until the study is closed by the IRB.   For 
example, if there are 10 participants enrolled in the trial, then only 2 participants will be 
required to be reviewed by the DSA.  
 
The DSA will send both a Monitoring Visit Report (MVR) and an Action Item Report 
(AIR) to the study team within 20 business days after the monitoring visit is complete 
for the study team to resolve all action items from the Action Item Report (AIR) report 
within 8 weeks. The due date for the completion of the action items may be extended 
for up to an additional 2 months for extenuating circumstances, if approved by the 
DSMC.  The AIR report must be completed by the study team prior to the next 
monitoring review of this study.  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.  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 (or a total of 10 
participants have been reviewed).  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.   
3.
Review and Oversight Requirements 
3.1
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 

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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. 
3.2
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 
Med Watch forms and information: 
www.fda.gov/medwatch/getforms.htm  

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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.   
3.3
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. 
Data and Safety Monitoring Committee Contacts: 
 Katie Kelley, MD (DSMC Chair) 
 
 
  
 
  
 
  UCSF HDFCCC 
  San Francisco, CA 94158 
John McAdams (DSMC Director)  
 
 
UCSF HDFCCC 
San Francisco, CA 94158