A Phase 2b double-blind, randomized, low-dose comparator-controlled clinical trial to assess the efficacy and safety of PEX010 in psilocybin-assisted psychotherapy for the treatment of adjustment disorder due to incurable cancer diagnosis

INTERVENTION: This Phase 2b study is a double‐blind, 1:1:1 randomized, study to assess the efficacy, safety and tolerability of 25 mg, 10 mg and 1 mg [low‐dose comparator] PEX010 in participants with adjustment disorder (AjD) following an incurable cancer diagnosis. The study will consist of a combination of clinic visits and telehealth visits and will involve the following study sequence: A screening visit (approximately 3 hours): within Day‐28 to ‐2 Visit at the clinic for continued eligibility and baseline assessments: Day ‐1 (1‐2 hours) PAP cycle: Day 1 to Day 28 In Clinic Visits: Day 1, 13, 14, 15, 84 Telehealth appointments: Day 7, Day 21, Day 28, Day 56, Day 168 and Day 253 (Psychiatrist/Psychologist/Psychotherapist): Preparatory therapy session: Day 1, Day 7, Day 13 (approximately 1 hour) ‐ Participants will attend three preparatory sessions (one virtual (Day 7) telehealth and two in‐person (Day 1, Day 13)) in the two weeks prior to being treated with psilocybin. Face to face appointment at clinic to be conducted with a suitably trained therapist will occur on Day 1 and Day 13, whilst a telehealth appointment with the therapist will occur on Day 7. The therapist will support the participant to establish intentions and goals, to be prepared for a range of potential effects of the psilocybin and have sufficient information to approach the intervention with an open mind. Face to face appointment at clinic to be conducted with a suitably trained therapist (Psychiatrist/Psychologist/Psychotherapist). Drug administration: Day 14 (approximately 8 hours). Participants will receive a single administration of PEX010 (capsule) under medical supervision on Day 14. Participants will be supported through the acute effects of the psilocybin by a suit CONDITION: Cancer ‐ Any cancer Mental Health ‐ Other mental health disorders Mental Health;Incurable Cancer;Adjustment Disorder; ; Mental Health ; Incurable Cancer ; Adjustment Disorder PRIMARY OUTCOME: To assess the change in anxiety severity in participants with AjD due to an incurable cancer diagnosis, as measured by HAM‐A.[Hamilton Anxiety Rating Scale Comparison between treatment groups in the change from baseline in the HAM‐A total score at Week 12 after a single PAP cycle.] To assess the safety and tolerability of a single dose of PEX010 (25 mg, 10 mg and 1 mg [low‐dose comparator]) in people with AjD with an incurable cancer diagnosis.[Vital signs ‐ systolic and diastolic blood pressure assessed using a digital sphygmomanometer. Pulse rate assessed using a pulse oximeter. Respiratory rate assessed using by auscultating the chest to count breaths for 1 minute and body temperature will be assessed by using remote ear thermometers.; Tolerability as assessed through compliance and participant withdrawal rate.; Common side affects at 25mg(>20%) include:; 1) Increased anxiety, particularly at the onset of the drug effects; 2) Mild‐moderate increase in heart rate; 3) Visual hallucinations; 4) Transient headaches, lasting for one to two days (maximum) post‐dosing; Participant compliance will be assessed with session attendance checklist and withdrawal rate will be assessed via study records. Assessment of Day 14 (dosing day) vital signs (pre‐dose and prior to discharge). ; ; ] To assess the safety and tolerability of a single dose of PEX010 (25 mg, 10 mg and 1mg [low‐dose comparator]) in people with AjD with an incurable cancer diagnosis[Sheehan Suicide Tracking Scale (S‐STS) Assessment of suicidality using the S‐STS (baseline, Day 14 (dosing day), 4, 8, and 12‐weeks and 6‐ and 9‐months post‐randomization).] SECONDARY OUTCOME: To assess the change in anxiety severity after receiving PAP in participants with AjD and an incurable cancer diagnosis[Hamilton Anxiety Rating Scale (HAM‐A) Comparison between treatment groups after a single PAP cycle of change from baseline in the HAM‐A total score at Day 15, Week 4, Week 8, and at 3‐ and 6‐months post‐treatment.] To assess the change in depression severity after receiving PAP in participants with AjD and an incurable cancer diagnosis.[Hamilton Depression Rating Scale (HAM‐D) Comparison between treatment groups after a single PAP cycle: ; Change from baseline in HAM‐D at Day 15, Week 4, Week 12, Week 8, and at 3‐ and 6‐months post‐treatment. ; ] To assess the change in depression severity after receiving PAP in participants with AjD and an incurable cancer diagnosis[Hospital Anxiety and Depression Scale Change from baseline in HADS at Day 15, Week 4, Week 8, Week 12 and at 3‐ and 6‐months post‐treatment.] To assess the efficacy of PAP in changing severity of AjD for participants with an incurable cancer diagnosis.[Composite Secondary Outcome: Adjustment Disorder ‐ New Module 20 (ADNM‐20); Demoralization Scale Comparison between treatment groups after a single PAP cycle: ; * Change from baseline in the ADNM‐20 at Day 15, Week 4, Week 8, Week 12, and at 3‐ and 6‐months post‐treatment. ; * Percentage of participants who achieve ‘remission’ of AjD defined by ADNM‐20 score of 47.5 or less and Distress Thermometer Score <4 at Week 12 after 1 cycle. ; * Percentage of participants who achieve ‘remission’ of AjD defined by ADNM‐20 score of 47.5 or less and Distress Thermometer Score<4 at Week 12 after a 2nd cycle. ; * Change from baseline in the Demoralization Scale at Day 15, Week 4, Week 8, Week 12, and at 3‐ and 6‐months post‐treatment. ; ; ] INCLUSION CRITERIA: To be eligible for study entry participants must satisfy all of the following criteria: 1. Screening AjD diagnosis (ICD‐11), as defined by an ADNM‐20 score greater than or equal to 47.5 , a score of greater than or equal to 4 on the Distress Thermometer and psychiatrist’s assessment via Mini International Neuropsychiatric Inventory (MINI). 2. Screening HAM‐A Score greater than or equal to 18 (moderate anxiety). 3. Adults aged 18 to 80 years. 4. Diagnosed with incurable cancer (exempting those cancers listed in the exclusion criteria) and a minimum life‐expectancy of 12 months in the opinion of the treating physician, with performance status of 0‐2 on the Eastern Cooperative Oncology Group (ECOG) scale. 5. Agrees not to commence any new psychiatric medications or psychotherapies from Screening to Week 12. 6. Able to communicate well and follow study procedures, judged as sufficiently competent with the English language by the investigator, abl