## Protocol Section
### Identification Module
**NCT ID:** NCT06416085

**Brief Title:** Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) Therapy for Patients With Advanced Cancer

**Official Title:** Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) Therapy for Patients With Advanced Cancer: A Phase II Open-Label Trial

#### Organization Study ID Info
**ID:** PEARL
#### Organization
**Class:** OTHER
**Full Name:** University Health Network, Toronto
#### Secondary ID Infos
**Domain:** University Health Network
**ID:** 21-5781
**Type:** OTHER
### Status Module
#### Completion Date
**Date:** 2026-06-15

**Type:** ESTIMATED

#### Last Update Post Date
**Date:** 2024-05-28

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-24

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2026-01-15

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-06-01

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-16
**Type:** ACTUAL
**Study First Submit Date:** 2024-01-14
**Study First Submit QC Date:** 2024-05-14
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** University Health Network, Toronto

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** The PEARL Pilot is a phase II open-label trial. Participants will receive a single high-dose (25 mg) of psilocybin in the context of Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) therapy.

**Detailed Description:** Individuals with advanced cancer often experience high levels of distress due to physical suffering, difficult treatment decisions, social isolation, and fear of death. While there are many treatment options for the management of physical symptoms associated with cancer, there are relatively few standard treatment approaches to help patients deal with psychological and existential suffering. Over the past decade, research has shown that psychotherapies incorporating existential, attachment and relational approaches can address the specific needs and challenges of the advanced cancer population and thus help to reduce distress. Simultaneously, recent research has shown that psilocybin-assisted psychotherapy, in which, an individual ingests the psychoactive drug within the carefully monitored therapeutic setting, can reduce end-of-life distress and greatly benefit those with advanced disease. The multidisciplinary team has combined these two evidence-based approaches into what the team calls Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) therapy. PEARL therapy combines elements from psilocybin-assisted psychotherapy, including preparatory therapy sessions, a high-dose drug session, and integration sessions, with important elements from manualized individual psychotherapies designed for patients with advanced cancer. This study will assess the feasibility, acceptability, and safety of PEARL therapy among patients with advanced cancer. This study will yield important information about the feasibility of this type of therapy and contribute to the growing research around the efficacy of psychedelic-assisted therapies. This type of therapy has the potential to improve quality of life among those with advanced disease and careful research is needed to build upon previous findings to outline the necessary components of therapy and guide public policy, legislation, and clinical guidelines.

### Conditions Module

**Conditions:**

- Advanced Cancer

- Stage IV Solid Tumor Cancer

- Stage IV Sarcoma of Bone

- Stage IV Lymphoma

- Stage IV Melanoma

- Endocrine Cancer

**Keywords:**

- Advanced Cancer

### Design Module

#### Design Info

**Allocation:** NA

**Intervention Model:** SINGLE_GROUP

##### Masking Info

**Masking:** NONE

**Primary Purpose:** SUPPORTIVE_CARE

#### Enrollment Info

**Count:** 15

**Type:** ESTIMATED

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Intervention Names:**

- Drug: Psilocybin

**Label:** Psilocybin

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Psilocybin

**Description:** Single high-dose (25mg) capsule of psilocybin taken orally in the context of Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) therapy

**Name:** Psilocybin

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** Used to assess feasibility of PEARL therapy.

**Measure:** Recruitment feasibility as assessed by the number of patients who consent/number of patients who meet eligibility criteria.

**Time Frame:** 24 months

**Description:** Used to assess feasibility of PEARL therapy.

**Measure:** Retention feasibility as assessed by the number of patients completing primary endpoint measures/number of patients consented.

**Time Frame:** 24 months

**Description:** Used to assess feasibility of PEARL therapy.

**Measure:** Adherence feasibility as assessed by the number of patients completing all PEARL sessions/number of patients consented.

**Time Frame:** 24 months

**Description:** Participants will be interviewed regarding their experiences with PEARL, including acceptability and perceived positive and negative effects of the intervention, with a semi-structured interview guide.

**Measure:** Acceptability of PEARL therapy from the perspective of advanced cancer patients obtained through qualitative interviews.

**Time Frame:** 24 months

**Description:** Safety will be assessed throughout the trial. Adverse events (AEs) attributed to psilocybin will be monitored for and recorded after the psilocybin session. This study will use CTCAE v5.0 to assess AEs.

Serious adverse events (SAEs) will be tracked until study completion and will be defined as any adverse drug experience that: results in death; that is life-threatening (i.e. any AE that places the participant, in the view of the investigators, at immediate risk of death from the reaction as it occurs); requires hospital admission; results in persistent or significant disability (i.e. a substantial disruption of a person's ability to conduct normal life functions); or may jeopardize the participant or necessitate medical intervention to prevent one of the aforementioned criteria.

**Measure:** Safety of PEARL therapy

**Time Frame:** 24 months

#### Secondary Outcomes

**Description:** The Death and Dying Distress Scale (DADDS) is a 15-item self-report measure designed for populations facing imminent death and addresses fears about the dying process, and about lost opportunities and self-perceived burden placed on others as a result of impending mortality. Total score range is 0 to 75. Higher scores indicate greater death-related distress.

**Measure:** Patient perspectives on the clinical relevance of potential PEARL therapy outcomes: Death anxiety in advanced cancer patients as assessed with the DADDS

**Time Frame:** 24 months

**Description:** The Patient Health Questionnaire-9 (PHQ-9) is a 9-item self-report scale measuring depressive symptoms. Total score range is 0 to 27. Higher scores indicate greater severity of depression.

**Measure:** Patient perspectives on the clinical relevance of potential PEARL therapy outcomes: Depressive symptoms as assessed with the PHQ-9

**Time Frame:** 24 months

**Description:** The Generalized Anxiety Disorder-7 (GAD-7) is a 7-item self-report scale used to screen for and measure anxiety symptoms. Total score range is 0 to 21. Higher scores indicate higher levels of anxiety.

**Measure:** Patient perspectives on the clinical relevance of potential PEARL therapy outcomes: Anxiety symptoms as assessed with the GAD-7

**Time Frame:** 24 months

**Description:** The Demoralization Symptoms (DS) is a 24-item self-report measure that assesses loss of meaning and purpose, disheartenment, and helplessness. Total score range is 0 to 96. Higher scores indicate higher levels of demoralization.

**Measure:** Patient perspectives on the clinical relevance of potential PEARL therapy outcomes: Loss of meaning and purpose, disheartenment and helplessness as assessed with the DS

**Time Frame:** 24 months

**Description:** The Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (FACIT-Sp) is a 12-item scale designed to measure important aspects of spirituality including sense of meaning in one's life, harmony, peacefulness and a sense of comfort and strength from one's faith. Total score range is 0 to 48. Higher scores indicate higher spiritual well-being.

**Measure:** Patient perspectives on the clinical relevance of potential PEARL therapy outcomes: Overall measure of spiritual well-being, meaning/peace and faith as assessed with the FACIT-Sp

**Time Frame:** 24 months

**Description:** The Quality of Life at the End of Life-Cancer (QUAL-EC) is a 17-item measure that includes subscales which assess symptom impact, preparation for end of life (i.e., the extent to which the family is prepared and financial plans have been made), relationship with healthcare providers (i.e., the extent to which patients feel informed and are able to participate in decisions about their care) and sense of life completion (i.e., being able to share important things and feel connected to others). For Symptom Control, score range is 3 to 15, with higher scores reflecting greater symptom control; for the Relationship with Healthcare Provider, score range is 5 to 25, with higher scores reflecting a better relationship with healthcare providers; for the Preparation for End-of-Life, score range is 4 to 20, with higher scores reflecting greater preparation for end-of-life; and the for Life Completion, score range is 5 to 25, with higher scores reflecting a greater sense of life completion.

**Measure:** Patient perspectives on the clinical relevance of potential PEARL therapy outcomes: Broad quality of life construct in patients facing end of life as assessed with the QUAL-EC

**Time Frame:** 24 months

**Description:** The Schedule of Attitudes Toward Hastened Death (SAHD) is a 20-item self-report measure of desire for death in the medically ill. Total score range is 0 to 20. Higher scores indicate greater desire for death.

**Measure:** Patient perspectives on the clinical relevance of potential PEARL therapy outcomes: Desire for death in the medically ill as assessed with the SAHD

**Time Frame:** 24 months

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

1. \>18 years of age;
2. Ability to speak and read English (patient to provide written informed consent and participate in PEARL intervention, as determined by study personnel);
3. No cognitive impairment indicated in medical record or by attending oncologist or palliative care physician;
4. Confirmed diagnosis of stage IV solid tumour cancers, sarcoma, endocrine, melanoma cancers, or stage 4 lymphoma with expected survival of greater than 6 months as determined by their oncologist or palliative care physician;
5. At least mild depressive symptoms, defined as \>8 on the Patient Health Questionnaire-9 (PHQ-9) (Kroenke et la., 2001);
6. Interest in and ability to participate in and complete the PEARL intervention and protocol as outlined;
7. Normal hepatic functioning as determined by prior medical history or/and screening bloodwork (INR\<1.5, Aspartate aminotransferase/Alanine Aminotransferase (AST/ALT) \< 2x upper limit of normal, normal range bilirubin, platelets \> 150)
8. Normal renal functioning as determined by prior medical history or/and screening bloodwork (eGFR\>45)
9. Participants who are sexually active and could become pregnant must be using effective birth control (per their physician), prior to study entry, during study participation, and for the duration of the study. Participants who are sexually active and could inseminate a partner must agree to use effective birth control after psilocybin administration until the end of study. For participants of child-bearing potential, a negative serum pregnancy test result is required at screening. A urine pregnancy test will be administered on the morning of psilocybin administration for applicable participants. Participants cannot be pregnant or nursing through the duration of the study;
10. If using prescribed medications or other substances, participants must agree to refrain from taking them if instructed by study investigators. These include:

    * not using any non-prescription medication, nutritional supplement, or herbal supplement except when approved by the treatment team (exceptions will be evaluated by the Investigator and will include acetaminophen, non-steroidal anti-inflammatory drugs, and common doses of vitamins and minerals),
    * not using nicotine for at least 2 hours before psilocybin administration, and not again until approximately 7 hours after psilocybin administration,
    * consuming approximately the same amount of caffeine-containing beverages (e.g., coffee, tea) that they consume on a usual morning before arriving at the treatment centre for the psilocybin session day,
    * not taking any as needed medications on the mornings of psilocybin sessions (with the exception of daily and as needed opioid pain medication),
    * refraining from using any psychoactive drugs, including alcoholic beverages, within 24 hours of the psilocybin administration.
11. Participants must have someone drive them after the session to where they are staying (home, hotel or another location), because psilocybin may affect their alertness and concentration on the evening of the dosing session.

Exclusion Criteria:

1. Cancer of the brain or metastasis to the brain;
2. Symptoms consistent with delirium, psychosis, or other symptoms judged to be incompatible with establishment of rapport or safe exposure to psilocybin;
3. A history of past intolerability of psilocybin or other psychedelics;
4. Past/present psychiatric diagnoses including bipolar disorder, psychotic disorders, active substance use disorders or suicidality (as distinguished from desire for hastened death or readiness for death, per the discretion of the study team);
5. If participant is under 30 years of age and has first degree relative with a primary psychotic disorder;
6. Severe hypertension (defined as systolic blood pressure \>140/or diastolic pressure \>90) based on two readings on the same day. If the second reading remains over 140/90 patient can be brought in for another reading on a different day. Patients can be re-screened for participation once blood pressure is adequately controlled;
7. Known paraneoplastic syndrome or "ectopic" hormone production by the primary tumor if incompatible with psilocybin, determined in consultation with the study palliative care physician. Patients could be enrolled if it is determined that the patient's condition is compatible with psilocybin administration.
8. Cardiovascular conditions including uncontrolled hypertension, angina, a clinically significant ECG abnormality (e.g., atrial fibrillation without rate control), transient ischemic attack in the last six months, stroke, peripheral or pulmonary vascular disease (no active claudication);
9. Uncontrolled epilepsy or history of seizures in past 6 months;
10. Participants with diabetes who are unable to skip a meal (lunch), or whose diabetes requires administration of medication more than twice daily, or who have had symptomatic hypoglycemia within the prior 30 days
11. GI bleed in last 6 months;
12. Use of other agents that would be inappropriate to take with psilocybin in the judgement of the investigator. These agents may include psychoactive prescription medications (e.g., benzodiazepines, lithium, Selective serotonin reuptake inhibitors), medications having a primary pharmacological effect on serotonin-2a (5-HT2A) receptors (e.g., olanzapine), or medications that are monoamine oxidase (MAO) inhibitors, any potent metabolic inducers (e.g. rifamycin, rifampin, rifabutin, rifapentine, carbamazepine, phenytoin, phenobarbital, nevirapine, efavirenz, taxol, dexamethasone, St John's wort) or inhibitors (e.g. HIV protease inhibitors, itraconazole, ketoconazole, erythromycin, clarithromycin, troleandomycin).

Of note, in suitable patients, these medications may be paused or tapered between study enrolment and prior to the start of the intervention when it is deemed safe to do so. A safe and appropriate tapering regimen will then be developed based on the particular medication, on a case-by-case basis. If taking an MAO inhibitor, the psilocybin session will not be conducted until at least 5 half-lives of the agent have elapsed after the last dose. Patients prescribed opioids will be allowed to take their usual dose regimen for analgesia, including the use of as needed analgesic medications on psilocybin session days.

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** UHNPPRG@uhn.ca

**Name:** Sarah Hales, MD

**Phone:** 416-340-4800

**Phone Ext:** 8051#

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Toronto

**Contacts:**

***Contact 1:***

- **Name:** Sarah Hales, MD

- **Role:** CONTACT

***Contact 2:***

- **Name:** Sarah Hales, MD

- **Role:** PRINCIPAL_INVESTIGATOR

***Contact 3:***

- **Name:** Emma Hapke, MD

- **Role:** PRINCIPAL_INVESTIGATOR

***Contact 4:***

- **Name:** Daniel Rosenbaum, MD

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** Canada

**Facility:** Princess Margaret Cancer Centre

**State:** Ontario

**Zip:** M5G 2M9

#### Overall Officials

**Official 1:**

**Affiliation:** University Health Network, Toronto

**Name:** Sarah Hales, MD

**Role:** PRINCIPAL_INVESTIGATOR

### References Module

#### References

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**PMID:** 19843620

**Citation:** Breitbart W, Rosenfeld B, Gibson C, Pessin H, Poppito S, Nelson C, Tomarken A, Timm AK, Berg A, Jacobson C, Sorger B, Abbey J, Olden M. Meaning-centered group psychotherapy for patients with advanced cancer: a pilot randomized controlled trial. Psychooncology. 2010 Jan;19(1):21-8. doi: 10.1002/pon.1556.

**PMID:** 19274623

**Citation:** Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016 Dec;30(12):1181-1197. doi: 10.1177/0269881116675513.

**PMID:** 27909165

**Citation:** Grossman CH, Brooker J, Michael N, Kissane D. Death anxiety interventions in patients with advanced cancer: A systematic review. Palliat Med. 2018 Jan;32(1):172-184. doi: 10.1177/0269216317722123. Epub 2017 Aug 8.

**PMID:** 28786328

**Citation:** Kissane DW, Wein S, Love A, Lee XQ, Kee PL, Clarke DM. The Demoralization Scale: a report of its development and preliminary validation. J Palliat Care. 2004 Winter;20(4):269-76.

**PMID:** 15690829

**Citation:** Krause S, Rydall A, Hales S, Rodin G, Lo C. Initial validation of the Death and Dying Distress Scale for the assessment of death anxiety in patients with advanced cancer. J Pain Symptom Manage. 2015 Jan;49(1):126-34. doi: 10.1016/j.jpainsymman.2014.04.012. Epub 2014 May 28.

**PMID:** 24878066

**Citation:** Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001 Sep;16(9):606-13. doi: 10.1046/j.1525-1497.2001.016009606.x.

**PMID:** 11556941

**Citation:** Lo C, Hales S, Zimmermann C, Gagliese L, Rydall A, Rodin G. Measuring death-related anxiety in advanced cancer: preliminary psychometrics of the Death and Dying Distress Scale. J Pediatr Hematol Oncol. 2011 Oct;33 Suppl 2:S140-5. doi: 10.1097/MPH.0b013e318230e1fd.

**PMID:** 21952572

**Citation:** Morita T, Murata H, Kishi E, Miyashita M, Yamaguchi T, Uchitomi Y; Japanese Spiritual Care Task Force. Meaninglessness in terminally ill cancer patients: a randomized controlled study. J Pain Symptom Manage. 2009 Apr;37(4):649-58. doi: 10.1016/j.jpainsymman.2008.04.017. Epub 2008 Oct 1.

**PMID:** 18834700

**Citation:** Rodin G, Lo C, Mikulincer M, Donner A, Gagliese L, Zimmermann C. Pathways to distress: the multiple determinants of depression, hopelessness, and the desire for hastened death in metastatic cancer patients. Soc Sci Med. 2009 Feb;68(3):562-9. doi: 10.1016/j.socscimed.2008.10.037. Epub 2008 Dec 7.

**PMID:** 19059687

**Citation:** Rodin G, Lo C, Rydall A, Shnall J, Malfitano C, Chiu A, Panday T, Watt S, An E, Nissim R, Li M, Zimmermann C, Hales S. Managing Cancer and Living Meaningfully (CALM): A Randomized Controlled Trial of a Psychological Intervention for Patients With Advanced Cancer. J Clin Oncol. 2018 Aug 10;36(23):2422-2432. doi: 10.1200/JCO.2017.77.1097. Epub 2018 Jun 29.

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## Derived Section

### Condition Browse Module - Ancestors

- ID: D000009371

- Term: Neoplasms by Site

- ID: D000004700

- Term: Endocrine System Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: All

- Name: All Conditions

- Abbrev: BC15

- Name: Blood and Lymph Conditions

- Abbrev: BC20

- Name: Immune System Diseases

- Abbrev: BC17

- Name: Skin and Connective Tissue Diseases

- Abbrev: BC19

- Name: Gland and Hormone Related Diseases

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M15327

- Name: Sarcoma

- Relevance: LOW

- As Found: Unknown

- ID: M11220

- Name: Lymphoma

- Relevance: LOW

- As Found: Unknown

- ID: M11528

- Name: Melanoma

- Relevance: LOW

- As Found: Unknown

- ID: M7863

- Name: Endocrine Gland Neoplasms

- Relevance: HIGH

- As Found: Endocrine Cancer

- ID: M7862

- Name: Endocrine System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T5284

- Name: Soft Tissue Sarcoma

- Relevance: LOW

- As Found: Unknown

- ID: T3543

- Name: Lymphosarcoma

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000009369

- Term: Neoplasms

- ID: D000004701

- Term: Endocrine Gland Neoplasms

### Intervention Browse Module - Ancestors

- ID: D000006213

- Term: Hallucinogens

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000011619

- Term: Psychotropic Drugs

### Intervention Browse Module - Browse Branches

- Abbrev: PsychDr

- Name: Psychotropic Drugs

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M14419

- Name: Psilocybin

- Relevance: HIGH

- As Found: Cover

- ID: M9305

- Name: Hallucinogens

- Relevance: LOW

- As Found: Unknown

- ID: M14474

- Name: Psychotropic Drugs

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000011562

- Term: Psilocybin

### Misc Info Module

- Version Holder: 2024-05-31
