Ketamine-assisted Therapy for Patients With Pancreatic Ductal Adenocarcinoma

Study Overview
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Brief Summary
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This clinical trial evaluates whether it is possible to use a single dose of oral liquid ketamine (ingested by mouth) in combination with talk therapy to treat moderate to severe demoralization in patients with pancreatic ductal adenocarcinoma (PDAC) who take opioids for cancer-related pain. PDAC patients often suffer from high rates of psychosocial distress and pain. Symptoms of anxiety are highly prevalent among PDAC patients. While opioid analgesia (pain reliever) succeeds in managing some symptoms, chronic opioid therapy is associated with significant adverse effects, underscoring a need to identify alternative interventions in the treatment of PDAC-associated pain. PDAC patients frequently suffer from existential distress. Demoralization is a form of existential distress that is common among people with serious medical illnesses; it is characterized by poor coping with stressful events, and a loss of meaning and purpose in life. Talk therapy is a form of psychological treatment during which patients discuss problems, thoughts, and feelings. Ketamine has demonstrated efficacy for the treatment of depression, suicidality, and pain in non-cancer patients. This study may help researchers learn whether both ketamine and talk therapy may improve psychosocial distress and pain, as well as decreases in opioid analgesic use in patients with PDAC who take opioids for cancer-related pain.

Detailed Description
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PRIMARY OUTCOMES: I. To assess the feasibility of Meaning and Purpose therapy combined with oral ketamine (K-MaP) in demoralized participants. SECONDARY OUTCOMES: I. To characterize the preliminary safety and tolerability of K-MaP in demoralized participants with pancreatic ductal adenocarcinoma. II. To assess the magnitude and durability of improvement from randomization in psychosocial distress. III. To assess the magnitude and durability of improvement from randomization in pain. IV. To assess the magnitude of change from randomization in opioid analgesic use. V.. To assess the magnitude and durability of change from randomization in interoceptive awareness EXPLORATORY OBJECTIVES: I. To assess how the participant's subjective experiences with ketamine may be related to clinical outcomes. II. To assess how participants' stage of PDAC may be related to clinical outcomes. OUTLINE: Adult pancreatic ductal adenocarcinoma (PDAC) participants receiving care at the Helen Diller Family Comprehensive Cancer Center (HDFCCC) will be randomized in a 1:1 ratio to one of two double-blinded conditions consisting of a single drug treatment and several therapy sessions, for up to 7 weeks. Participants will be followed up to 35 days (+/-2 days) after ketamine administration.

Official Title
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Pilot Study of Ketamine-assisted Talk Therapy for Demoralization in Patients With Pancreatic Ductal Adenocarcinoma and Pain

Conditions
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Pancreatic Ductal Adenocarcinoma, Pain, Acute

Intervention / Treatment
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* Drug: Ketamine
* Drug: Ketamine Injectable Product
* Behavioral: Meaning and Purpose therapy
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have a diagnosis of pancreatic ductal adenocarcinoma (PDAC) of any stage. 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. Must be 18 years or older. Must speak English and/or Spanish Must have a Palliative Performance Score (PPS) v. 2.0 greater than or equal to 40%. Must be able to swallow liquid oral medication. Clinically significant demoralization as assessed by the Demoralization Scale-II (DS-II). Must have used any opioid-based analgesia for cancer-related pain in the last 7 days (at time of screening). Must discontinue the following medications and refrain from taking following medications for the duration of study participation (participants who require these medications will be taken off study): Antipsychotics as-needed (PRN) anxiolytics. Note: Benzodiazepine use may be allowed if used in a regular, scheduled way. Consultation with the Principal Investigator is recommended. Dopamine agonists Lithium 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. 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 participants decide to engage in penile-vaginal intercourse during the course of the study. Must agree to the following life-style considerations: 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. 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). Abstain from alcohol for 24 hours before receiving ketamine. Abstain from using any nicotine-containing products (including nicotine patches) for 3 hours before receiving ketamine. If cannabis products are used regularly, participants will be asked to continue using regular amount, but will be asked not to use cannabis within 24 hours prior to receiving ketamine. If prescribed a regular dose of benzodiazepines, participants will be asked not to take medication the morning of the ketamine administration visit. If taking any psychostimulants (e.g., methylphenidate), participants will be asked not to take psychostimulant drugs (other than caffeine) the morning of the ketamine administration visit. Participants will be advised to maintain usual opioid regimen. 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 risk of respiratory depression from ketamine). Exclusion Criteria: Has a known allergic or severe reactions to the non-psychoactive components of liquid ketamine. Has received treatment with another investigational drug or intervention within 1 month of signing Informed Consent Form (ICF). Is deemed by clinical judgment of the study investigators to be unsafe for undergoing the intervention. Has a history of intra-cerebral hemorrhage. Has cognitive impairment sufficient to impede the ability to complete study tasks. Has had delirium/encephalopathy within 3 months of signing ICF. Has a history of intracranial hemorrhage. Has had a stroke (embolic) within 12 months of signing ICF. Has had a seizure within 6 months of signing ICF. Currently has an intracranial mass (e.g., primary tumor or brain metastasis). Has an advanced stage of a neurologic disease that puts participants at elevated risk for psychosis (e.g., Parkinson or Huntington disease). Has a history of a primary psychotic disorder or primary bipolar disorder I or II (determined by Quick Structured Clinical Interview for Diagnostic and Statistical Manual version 5 Disorders (QuickSCID-5)). Has a history of dissociative disorder. Recent, clinically significant suicidal ideation. Note: This does not include requesting medical aid in dying. Is currently receiving electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) or similar somatic therapies. Has baseline hypertension (≥140 SBP or ≥90 DBP), after repeated measurements. Note: Participants with hypertension that has been controlled by medication down to <140 Systolic blood pressure (SBP) and <90 diastolic blood pressure (DBP) will be allowed participate. Has a history of aneurysmal vascular disease or dissection (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation. Has had cardiac arrest within 12 months of signing ICF. Has had a myocardial infarction within 12 months of signing ICF. Has QTcf >450msec on 12-lead EKG. Note: Participants may qualify for the study if QTc 450-480 msec on one EKG, but then <=450 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. Has clinically significant arrhythmia defined as Ventricular fibrillation or ventricular tachycardia within 1 year of signing ICF 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. Atrial fibrillation, continuous Atrial fibrillation, intermittent, without rate or rhythm control Supraventricular tachycardia (SVT), without standard treatment Other clinically significant arrhythmias (e.g., Wolf Parkinson White) Has symptomatic congestive heart failure (NYHA Class II-IV) Has severe obstructive intracardiac abnormalities (e.g., aortic stenosis) Has any current condition where physical activity is associated with palpitations, anginal pain or syncope. Is unable to protect their own airway due to dysphagia, difficulty swallowing or a neurologic disease resulting in a risk of aspiration. Has a history of flash pulmonary edema within 12 months of signing ICF. Has a diagnosis of moderate or severe pulmonary hypertension. Needs supplemental oxygen (intermittent or continuous). Has current intractable nausea/vomiting/diarrhea. Has had a clinically significant GI bleed within 6 months of signing ICF. Meets the following laboratory parameters: Asymptomatic alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >=5x upper limit of normal (ULN). Symptomatic ALT or AST >= 2x ULN. Total bilirubin > 2x ULN (Gilbert syndrome is allowed) Alkaline phosphatase >5x ULN International Normalized Ratio (INR) > 3.0 Renal insufficiency (i.e., estimated glomerular filtration rate (eGFR) < 30 milliliter/minute (mL/min) /1.73 m^2 (using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation), Creatinine Clearance (CrCl) < 30 mL/min (using the Cockcroft-Gault Equation), or current dialysis)). Is currently pregnant or breastfeeding. Has insulin-dependent diabetes with diabetes-related hospitalization within 6 months of signing ICF.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A (K-MaP)<br>Participants will receive 0.5mg/kg of Ketamine orally with an equivalent quantity of placebo via an intramuscular injection on Day 0/Visit 4 and receive Meaning and Purpose (MaP) therapy 4 times, twice before ketamine administration (Day 0), and twice afterward. The duration of treatment for ketamine plus MaP (K-MaP) therapy is approximately up to 28 days. Participants will be followed up to 35 days (+/-2 days) after ketamine administration. | Drug: Ketamine<br>* Given orally (PO)<br>* Other names: Ketalar Hydrocholoride;Behavioral: Meaning and Purpose therapy<br>* In-person sessions<br>* Other names: Psychotherapy;Other: Placebo<br>* Given PO or IM<br>|
| Experimental: Group B (K-Map)<br>Participants will receive 0.5mg/kg of Ketamine IM with a placebo oral solution on Day 0/Visit 4 and receive Meaning and Purpose (MaP) therapy 4 times, twice before ketamine administration (Day 0), and twice afterward. The duration of treatment for ketamine plus MaP (K-MaP) therapy is approximately up to 28 days. Participants will be followed up to 35 days (+/-2 days) after ketamine administration. | Drug: Ketamine Injectable Product<br>* Given intramuscularly (IM)<br>* Other names: Ketalar Hydrocholoride;Behavioral: Meaning and Purpose therapy<br>* In-person sessions<br>* Other names: Psychotherapy;Other: Placebo<br>* Given PO or IM<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion eligible versus screened participants. | The rate of recruitment is defined as the proportion of eligible participants who participate compared to the number of total participants who were screened or signed consent but did not meet eligibility criteria will be reported. | Up to 28 days | 
| Proportion of participants who complete therapy | Proportion of enrolled participants completing K-MaP intervention and all Demoralization Scale II (DS-II) assessments will be reported. | Up to 49 days | 
| Frequency of participant responses to intervention acceptability | The participants will provide qualitative feedback on the acceptability of the intervention via a 20-minute interview with the study team upon study termination. Frequency of responses will be categorized and reported by arm. | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants reporting treatment-emergent adverse events | The percentage of participants in each arm reporting treatment-related adverse events will be reported. Pre-determined criteria for assessment of tolerability to K-MaP include zero treatment-related serious adverse events, and all other adverse events will be assessed using Common Terminology Criteria for Adverse Events version 5.0. | Up to 49 days | 
| Percentage of participants with clinically significant changes in blood pressure | At time of ketamine administration, participants blood pressure will be monitored for any clinically significant changes. The percentage of participants with a clinically significant change in blood pressure from pre-medication administration to end of study visit will be reported. | 1 day | 
| Percentage of participants with clinically significant changes in heart rate | At time of ketamine administration, participants heart rate will be monitored for any clinically significant changes. The percentage of participants with a clinically significant change in heart rate from pre-medication administration to end of study visit will be reported. | 1 day | 
| Mean scores on the Challenging Experience Questionnaire (CEQ) over time | The CEQ is a 26-item, self-reported 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]). Participants are asked to rate each item based on the degree to which each item was experienced. A higher total CEQ score indicates greater psychologically adverse reactions to psilocybin. | 1 day | 
| Mean clinician-rated scores on the Global Clinical impression of severity (CGI-S) over time | The CGI is a 3-item clinician-administered measure developed by the National Institute of Mental Health to assess clinical change in participants in psychopharmacology trials. This study will be using the Global Impression of Severity item (Considering your total clinical experience with participants 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 participants to assess change in demoralization. | Up to 49 days | 
| Proportion of participants with reported demoralization based on the Diagnostic Criteria in Psychosomatic Research (DCPR) Demoralization scale. | The DCPR is a structured, clinician-administered, interview regarding various psychosomatic conditions and will be administered to participants over the course of the study. Clinicians will record the rates of demoralization as present or not per participant | Up to 49 days | 
| Mean clinician-rated scores on the GRID-Hamilton Depression Rating Scale (GRID-HAMD) over time | The 6-item Hamilton Depression Rating Scale (HAMD-6) is a validated, brief, clinician-rated measure of the core symptoms of major depression. With permission from authors (the International Society for Central Nervous System Drug Development (ISCDD)) a modified, 6-items version of the HAMD-6 in the GRID-HAMD format to will be used by clinicians to create a brief, responsive and reliable measure of core depression symptoms of participants. Responses on the items will range from 0=absent; 1=mild; 2=moderate; 3=severe; 4=incapacitating and scores will be summed to create a total score. The higher the total score the more severe the depression symptoms of the participant. | Up to 49 days | 
| Mean scores on the Demoralization (DS-II) over time | The DS-II is a self-report measure of demoralization which consists of 16-items measuring events that occured over the past 2 weeks, which are scored on a 3-point scale ranging from 0 to 2. Scores are calculated by adding each item score, for a total score range of 0 to 32. Higher scores indicate a greater degree of demoralization. | Up to 49 days | 
| Mean scores on the Patient Health Questionnaire 9 (PHQ-9) over time | The Patient Health Questionnaire-9 (PHQ-9) is used to measure depression symptoms. The total Patient Health Questionnaire-9 (PHQ-9) score is calculated by combining the responses of the participant on questions addressing how bothered the participant has been by various problems over the past 2 weeks. Each of the 9 items is scored on a scale of 0 (Not bothered at all) to 4 (Nearly every day). A total score of 5-9='Mild Depression Symptoms, 10-14=Minor Depression, Major Depression (mild), or Dysthymia, 15-19=Major Depression, moderately severe, and >20=Major Depression. | Up to 49 days | 
| Mean scores on the Generalized Anxiety Disorder 7 (GAD-7) over time | The GAD-7 is a seven-item instrument that is used to measure or assess the severity of generalized anxiety disorder. The GAD-7 score is calculated by assigning scores of 0, 1, 2, and 3, to the response categories of not at all, several days, more than half the days, and nearly every day, respectively, and then adding together the scores for the seven questions. Scores of 5, 10, and 15 represent cut-points for mild, moderate, and severe anxiety, respectively. When used as a screening tool, further evaluation is recommended when the score is 10 or greater. | Up to 49 days | 
| Mean scores on the Functional Assessment of Chronic Illness Therapy Palliative Care, 14 Item Version (FACIT-Pal-14) (FACIT-Pal-14) over time | The FACIT-Pal-14 is a 14-item, self-report measure of quality of life in palliative care participants. The measure has a 7-day recall period with responses to items which fall on a 5-point Likert scale, with scores ranging from 0 = Not at all to 4 = Very much. Scores are summed to create a total score of 0 to 56, with higher scores indicating a greater quality of life. | Up to 49 days | 
| Mean scores on the Brief-Pain Inventory Short Form (BPI-SF) over time | The BPI-SF is a 9-item questionnaire used to assess the severity of pain and the impact of pain on activities of daily living over a recall period of 24 hours. Pain severity is assessed across four sub-scales; 'worst pain', 'least pain', 'average pain' and 'current pain'. A pain score for each subscale is presented separately. Scales are rated on a scale of 0 to 10 (0 = no pain; 10 = pain as bad as one can imagine). A composite score for pain severity is calculated as the mean of the four severity items. Question 9 comprises a 7-item interference scale. Questions assess the level to which pain interferes with general activity, walking, work, mood, enjoyment of life, relations with others and sleep on a scale of 0 to 10 (0 = does not interfere; 10 = completely interferes). Mean interference score will be calculated as an average of the seven subparts of question 9 where at least four of the seven items are completed. | Up to 49 days | 
| Proportion of participants reporting any use of opioids | Using the Morphine Milligram Equivalents (MME) calculation, participants cumulative daily dose of opioids will be calculated for the past 24 hours at each study visit. The proportion of participants with any reported opioid use at any of the study visits will be reported. | Up to 49 days | 
| Mean scores on the Multidimensional Assessment of Interoceptive Awareness, Version 2 (MAIA-2) | The MAIA-2 is a validated a widely used questionnaire to measure interoceptive awareness. This measure consists of 37-items using a 6-point Likert scale (0 = Never to 5 = Always). The MAIA-2 has demonstrated good internal consistency and reliability for the evaluation of clinical mind-body interventions, with higher scores indicating increased awareness. | Up to 49 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Medication assisted therapy