A Phase I/II Trial of UCB4594 in Participants With Advanced Cancer

Inclusion Criteria:

1. Written (signed and dated) informed consent and capable of co-operating withinvestigational medicinal product (IMP) administration and follow-up

2. Participant population: Histologically or cytologically proven advanced solidtumours (as specified below), refractory to conventional treatment, or for which noconventional therapy is considered appropriate by the Investigator or is declined bythe participant. Module A (dose escalation): Tumour types which have shown highlevels of human HLA-G expression (as reported in the literature): head and necksquamous cell carcinoma, non-small cell lung cancer, colorectal cancer,triple-negative breast cancer, renal cell cancer (clear cell only),oesophago-gastric cancer (excluding gastrointestinal stromal tumour), cervicalcancer, ovarian cancer, pancreatic cancer. N.B. Participants with small cell typecancers on histology/cytology are excluded. Pre-treatment biopsies are mandatory forall participants. Paired biopsies will be mandatory for participants from doses of 30 mg and higher. Participants must have disease amenable to biopsy (excluding bonemetastases) as deemed safe by the Investigator

3. Measurable disease, according to RECIST v1.1

4. Life expectancy of at least 12 weeks

5. Eastern Cooperative Oncology Group performance status of 0 or 1

6. Haematological and biochemical indices within defined ranges. These measurementsshould be performed to confirm the patient's eligibility to participate in the trial

7. Aged 18 years or over at the time consent is given. Participants aged 16-17 yearsmay be eligible for recruitment to the backfill cohorts in dose escalation onceadequate safety and toxicity data have been established in participants aged 18years or over. All relevant data will be reviewed and a decision on the inclusion ofparticipants aged 16-17 years will be made by the Trial Management Group

Exclusion Criteria:

1. Radiotherapy (except palliative), endocrine therapy (unless for non-malignantdisease), chemotherapy, targeted therapy or immunotherapy, or any other IMPs duringthe previous 4 weeks or 5 half-lives (whichever is shorter) before the first dose ofIMP

2. Ongoing toxicity of previous treatments >CTCAE Grade 1 (except alopecia of anygrade, stable Grade 2 peripheral neuropathy or hormone-replacement therapy (HRT)-managed endocrine disorders)

3. Patients with rapidly progressing / symptomatically deterioratingbrain/leptomeningeal metastases/untreated brain metastases are excluded. Patientswith previously treated brain metastases are eligible if they haven't had a seizureor a clinically significant change in neurological status or required steroids inthe last 2 weeks

4. Pregnant or breastfeeding female patients (or planning to breastfeed)

5. Women of childbearing potential. However, those not already pregnant orbreastfeeding (or who discontinue breastfeeding) and meet the following areeligible:

5.1. Have a negative serum pregnancy test within 7 days before enrolment and either:

5.2.1. Agree to a form of highly effective contraception plus a barrier method, or

5.2.2. Agree to sexual abstinence Effective from the negative pregnancy test, throughout the trial and for 10 monthsafter the last dose of UCB4594

6. Male patients with partners of childbearing potential. However, patients who meetthe following are eligible:

6.1. Agree to a barrier method of contraception or sexual abstinence

6.2. Males with pregnant or breastfeeding partners must use barrier methodcontraception to prevent exposure of the foetus or neonate

6.3. Non-vasectomised males must also ensure any partner of childbearing potentialuses highly effective contraception or agrees to sexual abstinence Effective from the date of the first dose of UCB4594, throughout the trial and for 5months after the last dose of UCB4594 N.B. Males must refrain from donating spermfor the same period

7. Surgery from which the patient has not yet recovered

8. High medical risk because of non-malignant systemic disease, including serious oruncontrolled infection (requiring intravenous antibiotics) or unexplained fever >38°C within 2 weeks prior to the first dose of UCB4594

9. Known to be serologically positive for hepatitis B virus, hepatitis C virus or humanimmunodeficiency virus

10. Active or suspected autoimmune disease, or any history of autoimmune condition thatrequired systemic corticosteroids or immunosuppressive agents. Patients who haveever had a transplant are excluded. This does not apply to patients with: vitiligo,alopecia, or type I diabetes mellitus, psoriasis not requiring chronic systemicimmunosuppressive treatment within the past 2 years, stable autoimmune-mediatedhypothyroidism on HRT, and Raynaud's syndrome

11. Are being treated with escalating or supraphysiologic doses of corticosteroids orimmunosuppressive agents. Participants with immunotherapy-related hypophysitisadequately treated with physiologic doses of steroids are not excluded. Use oftopical, ophthalmic, inhaled, intermittent steroid injections, and intranasalcorticosteroids are permitted

12. Hypersensitivity to the ingredients/excipients (including polysorbate 80) in UCB4594

13. History of significant toxicities from treatment of immune checkpoint inhibitors (CPIs) that necessitated permanent discontinuation (Patients who started oncombination CPI [e.g., ipilimumab/nivolumab] and had toxicity requiringdiscontinuation of one CPI [e.g., continued with nivolumab single agent] are notexcluded)

14. History of Grade ≥3 infusion-related reaction to monoclonal antibodies or similardrugs

15. Prior treatment with HLA-G, immunoglobulin-like transcript (ILT)2 or ILT4-targetingdrug

16. Live, attenuated vaccine within 28 days prior to the first dose of IMP

17. Increased risk due to tumour flare (e.g., an initial increase in tumour size thatmay lead to obstruction of airways, etc)

18. Significant active pulmonary disease or condition at screening, including:

18.1. Lymphangitis carcinomatosa

18.2. History of interstitial lung disease or pulmonary fibrosis

18.3. History of pulmonary inflammatory disease

19. Evidence of bleeding diathesis

20. Significant cardiovascular disease, defined as a history of: congestive heartfailure requiring therapy or left ventricular ejection fraction <40%, unstableangina pectoris or myocardial infarction within 6 months prior to entry, or currentpoorly controlled angina (symptoms weekly or more), clinically significant cardiacarrhythmia within 6 months prior to entry (asymptomatic atrial fibrillation orasymptomatic first-degree heart block permitted), or myocarditis. Presence ofsymptomatic or severe valvular heart disease. Baseline QT interval corrected byFridericia >450 msec for males and >470 msec for females on triplicateelectrocardiogram is ineligible

21. Participant in or plans to join another interventional trial

22. Other current malignancies. Cancer survivors who have undergone potentially curativetherapy for prior malignancy with no evidence of disease for 3+ years are eligible

23. Any other condition that, in the Investigator's opinion, means the trial is not inthe patient's best interest