A phase II trial of CY-101 in participants with adrenocortical cancer.

Inclusion criteria:
1. Written (signed and dated) informed consent and be capable of co-operating with CY-101 administration and follow-up
2. Histologically confirmed ACC that is either locally advanced and not amenable to surgical resection or metastatic, with evidence of disease progression post the most recent line of therapy
3. Participants must have received treatment with at least 1 line, but not more than 2 prior lines, of systemic therapy for established locally advanced or metastatic disease, and must have received mitotane therapy within these lines of therapy for advanced/metastatic disease (or as neoadjuvant/adjuvant therapy), delivered at an adequate dose as described below. A line of therapy is counted as any of the following: i) Mitotane monotherapy - The participant must have received this therapy, at least at the time of assessment of progression, at a therapeutic plasma level (defined as ≥14 mg/L) or at maximum individual tolerated dose; dose and limiting circumstances should be documented in patient files; - Suboptimal mitotane therapy is defined as treatment at plasma levels <14 mg/L or not at a maximum individual tolerated dose; such therapy is not counted as a line of therapy, and such therapy does not cause the patient to be eligible for the trial; ii) Chemotherapy with/without mitotane, and iii) Other anti-cancer systemic therapies (as monotherapies or combination therapies, e.g. in clinical trials). Participants must have relapsed within 1 year of neoadjuvant/adjuvant therapy for this to be considered a line of treatment.
4. At least 1 lesion that is objectively evaluable or measurable, according to itRECIST. Previously irradiated lesions cannot be counted as target lesions unless they have clearly progressed after radiotherapy. Participants also require at least 1 separate lesion(s) amenable for IT injection by a clinician or interventional radiologist under ultrasound-assisted guidance, including unresected and local recurrences of the primary adrenal tumour as well as lymph node, soft tissue and liver metastases. The primary tumour may also be injected if not previously resected. Lesions previously treated with methods directed at local control (stereotactic body radiation therapy, ablative procedures, liver-directed therapy, radiotherapy) can be injected if disease progression has been observed in the target lesion but will be considered non-injectable if they remain under persistent control without progression. Participants for Phase IIa must have sufficiently sized target lesion(s) for IT injection to accommodate delivery of the total 4 mL volume of CY-101, in the opinion of the radiologist.
5. Adequate tissue available for biomarker testing, from either archival tissue or pre-treatment biopsy. All participants must consent to paired pre- and on-treatment tumour biopsy sampling unless agreed with the CI to omit as deemed not feasible or medically unsafe, or if there is only 1 injectable lesion. The tumour biopsy must be from a lesion that will be injected but not from the lesion(s) which will be injected and monitored for efficacy.
6. Life expectancy of ≥12 weeks.
7. ECOG performance status of 0–2 (Appendix 1).
8. Haematological and biochemical indices within the ranges shown below. These measurements should be performed to confirm the patient’s eligibility to participate in the trial.Laboratory Test Value Required Hb ≥90 g/L, ANC ≥1.5×10^9/L, Platelet count ≥100×10^9/L ,Total bilirubin ≤1.5× ULN, If known Gilbert’s syndrome: total bilirubin ≤3× ULN, ALT and AST ≤2.5× ULN, or ≤5× ULN if raised due to presence of liver metastases Renal function – estimated creatine clearance ≥50 mL/min (Cockcroft-Gault) Albumin ≥28 g/L Coagulation – PT (or INR) and aPTT <1.5× ULN
9. Aged 18 years or over at the time consent is given.

Exclusion criteria:
1. Radiotherapy (except for palliative reasons), endocrine therapy, chemotherapy or other IMPs during the previous 28 days or 5 half-lives (whichever is longer) before first dose of CY-101. Continued treatment with mitotane during the trial for hormonal symptom control is permitted under the following circumstances: •	Participants who have received mitotane therapy before trial entry (in the adjuvant and/or established disease settings) can continue mitotane during the trial provided tumour recurrence/progression has been demonstrated, at mitotane therapeutic plasma level (≥14 mg/L) or at maximum individual tolerated dose.  •	Patients who have received suboptimal mitotane therapy, defined as treatment at plasma levels <14 mg/L or not at a maximum individual tolerated dose, are not eligible to continue with mitotane therapy during the trial. Mitotane plasma level monitoring must be maintained and documented during the trial.
2. Serologically positive for HBV or HCV. Patients with previous HCV exposure but no current infection are eligible to participate.
3. Known untreated HIV infection. Participants on established antiretroviral medication and who have well-controlled HIV infection/disease are eligible provided they meet all the following criteria: • On a stable antiretroviral regimen, without changes in drug or dose, for at least 4 weeks prior to the first dose of CY-101 and have a viral load of <400 copies per mL ≤28 days prior to the first dose of CY-101. • CD4+ T-cell count ≥350 cells/μL ≤28 days prior to first dose of CY-101. • Without a history of opportunistic infection within the last 12 months.
4. Allergy or hypersensitivity to any of the ingredients/excipients in the CY-101 formulation.
5. Significant cardiovascular disease, defined as: i) History of congestive heart failure requiring therapy (New York Heart Association III or IV [Appendix 6]) or LVEF <40% (moderate or severe); ii) History of unstable angina pectoris or myocardial infarction within 6 months prior to trial entry, or current poorly controlled angina (symptoms weekly or more); iii) Presence of symptomatic or severe valvular heart disease (severe by local echocardiographic criteria or American Heart Association/American College of Cardiology Stage C or D); iv) History of a clinically significant cardiac arrhythmia within 6 months prior to trial entry (asymptomatic atrial fibrillation or asymptomatic first-degree heart block are permitted).
6. Extensive radiotherapy to >25% of bone marrow within 12 weeks prior to the first dose of CY-101
7. Participating in or plans to participate in another interventional clinical trial while taking part in this Phase II trial of CY-101. Participation in an observational trial or interventional clinical trial that does not involve administration of an IMP and that would not place an unacceptable burden on the patient, in the opinion of the Investigator, would be acceptable.
8. Current malignancies of other types, with the exception of adequately treated cone biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivors who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for 5 years or more and are deemed at negligible risk for recurrence are eligible for the trial
9. Any congenital immunodeficiency syndrome.
10. Active autoimmune disease that has required systemic treatment in the 2 years prior to trial entry (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
11. Use of systemic corticosteroids (apart from replacement doses for endocrinopathy up to an equivalent of 10 mg QD prednisolone or 20 mg QD prednisolone if receiving mitotane concurrently) or other immunosuppressive treatments. Topical, ophthalmic, inhaled or intranasal steroids for pre existing diseases are allowed.
12. Prior treatment with a Wnt inhibitor.
13. Prior adverse reaction to cancer immunotherapy that required IV steroid treatment or other immunosuppressive treatment (oral, IV, subcutaneous) or that led to discontinuation of that treatment
14. Live, attenuated vaccine within 28 days prior to the first dose of CY-101.
15. Evidence of bleeding diathesis, or anticoagulant or antiplatelet therapy (excluding prophylactic low molecular weight heparin or low-dose aspirin).
16. High burden of metastatic disease defined as 4 or more organs involved with metastases or greater than 12 individual metastases including primary tumour as imaged on CT/MRI.
17. Patients with uncontrolled hormonal secretion (according to the judgement of the Investigator) e.g. Cushing’s or mineralocorticoid excess causing uncontrolled hypertension, diabetes, and hypokalaemia.
18. Any other condition that, in the Investigator’s opinion, would mean that the trial is not in the best interests of the patient.
19. Ongoing toxic manifestations of previous treatments greater than CTCAE Grade 1 (other than alopecia of any grade or Grade 2 peripheral neuropathy). Exceptions to this are any ongoing toxic manifestation that is stable and in the opinion of the Investigator, should not exclude the patient.
20. Any CNS metastases (unless patients had local therapy and are asymptomatic, radiologically stable for 4 weeks and have been off steroids for the last 4 weeks).
21. Women who are pregnant or breastfeeding (or planning to breastfeed).
22. Women of childbearing potential (A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Post-menopausal state is defined as no menses for 12 months without an alternative medical cause. A high FSH level in the post-menopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient). However, those patients who are not already pregnant or breastfeeding (or planning to breastfeed) are eligible provided they have a negative highly sensitive serum pregnancy test within 7 days before trial entry and agree to follow the trial’s contraceptive requirements (refer to Appendix 8).
23. Male patients with partners of childbearing potential (A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Post-menopausal state is defined as no menses for 12 months without an alternative medical cause. A high FSH level in the post-menopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient). However, those patients who agree to follow the trial’s contraceptive requirements (refer to Appendix 8) are eligible.
24. Major surgery from which the patient has not yet recovered.
25. At high medical risk because of non-malignant systemic disease, including active uncontrolled infection.