A Phase II, Multi-centre, Open Label, Randomised Study to Evaluate the Anti-tumour Activity of Roginolisib in Patients With Advanced/Metastatic Ocular/Uveal Melanoma

A Phase II open-label, randomised, parallel-arm study, which will assess the clinical efficacy of oral roginolisib (IOA 244 [roginolisib hemi-fumarate]) as monotherapy against a control of Investigator´s treatment choice in patients with advanced or metastatic uveal melanoma (UM).

This study will enrol approximately 85 male and female patients aged over 18 years with advanced or metastatic UM, who have progressed following at least 1 prior immunotherapy treatment. The disease must be measurable (i.e., at least 1 measurable lesion) as per RECIST v1.1 by Computerised Tomography (CT) scan or Magnetic Resonance Imaging (MRI).

Sex: ALL
Minimum Age: 18 Years
Healthy Volunteers: No
Age Groups: ADULT, OLDER_ADULT

Inclusion Criteria:

1. Male or female aged 18 years or older;
2. Histologically or cytologically proven diagnosis of advanced or metastatic UM or ocular melanoma (arising from ocular melanocytes regardless of intraocular location)
3. Patients who have progressed following at least 1 prior immunotherapy treatment for advanced or metastatic UM. For patients who are HLA-A*02:01 positive prior treatment should have included tebentafusp, if available or patients clinically suitable. Patients who have also received prior melphalan hepatic infusion may be included;
4. Presence of at least one lesion suitable for biopsy. Biopsies will be mandatory at Screening and C5D1 (see Sections 8.1.3 and 8.6 for more information);
5. Presence of at least one measurable lesion as per RECIST v1.1. Any lesion that is biopsied cannot be used as a measurable lesion for the purposes of RECIST v1.1 assessments;
6. ECOG performance status of 0 to 1;
7. Male or female patients of child-bearing potential must be willing to use highly effective forms of contraception (refer to APPENDIX 7 for details on highly effective methods of contraception and definitions of women of childbearing potential and of fertile men)
8. All other relevant medical conditions must be well managed and stable, in the Investigator’s opinion, for at least 28 days prior to first dose of roginolisib;
9. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.

Exclusion Criteria:

1. Inability to swallow oral medication;
2. a). History of a prior Grade 3 or 4 irAE or any grade ocular irAE from prior immunotherapy which did not respond to corticosteroid therapy or resolved with treatment interruptions and returned to at least Grade 1; b). Have not recovered from toxic effect(s) of prior therapy to ≤ Grade 1, other than alopecia or fatigue or neuropathy which must be ≤ Grade 1;
3. Presence of symptomatic or untreated CNS metastases or CNS metastases that require doses of corticosteroids within the prior 3 weeks to first dose of roginolisib. Patients with brain metastases are eligible if lesions have been treated with localised therapy and there is no evidence of progressive disease for at least 4 weeks prior to the first dose of IMP;
4. Abnormal liver enzymes defined as:

1. ALT or AST ≥ 3× upper limit of normal (ULN) (≥ 5× ULN in patients with liver metastases);
2. Total bilirubin ≥ 1.5 × ULN are excluded unless direct bilirubin is ≤ ULN. If there is no institutional ULN, then direct bilirubin must be < 40% of total bilirubin to be eligible (except patients with Gilbert syndrome);
5. Any other clinically significant out of range laboratory values;
6. Clinically significant cardiac disease or impaired cardiac function which may limit the patient´s participation in the clinical study. These may include unstable angina (i.e., not responsive to medical intervention), myocardial infarct in last 6 months, QTcF prolongation of more than 500 ms;
7. Evidence of interstitial lung disease or active, non-infectious pneumonitis, pulmonary fibrosis;
8. Active infection requiring systemic antibiotic therapy. Patients requiring systemic antibiotics for infection must have completed therapy at least 1 week prior to the first dose of IMP;
9. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection per institutional protocol;
10. Malignant disease, other than that being treated in this study (e.g., skin/cutaneous and/or mucosal melanoma). Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to first dose of IMP; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type;
11. Any medical condition that would, in the Investigator's or Sponsor's judgment, prevent the patient's participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results;
12. Treatment with anti-tumour medications or investigational drugs within 14 days or 5 half-lives (whichever is longer) of administration of first dose of IMP;
13. Major surgery within 2 weeks of the first dose of IMP (minimally invasive procedures such as bronchoscopy, tumour biopsy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery and are not exclusionary);
14. Radiotherapy within 4 weeks of the first dose of IMP, with the exception of palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumour mass;
15. Pregnant, likely to become pregnant, or lactating women.