A Safety, Pharmacokinetic and Clinical Activity Study of NUC-7738 in Patients With Advanced Solid Tumours and Lymphoma

Inclusion Criteria:

1. Provision of signed written informed consent

2. Solid tumour cohorts only (Phase I and Phase II; excluding NUC-7738 + pembrolizumabcohort): Histologically confirmed diagnosis of an advanced solid tumour withmeasurable disease as per RECIST v1.1 criteria and/or evaluable disease (evaluable:cytologically or radiologically detectable disease such as ascites, peritonealdeposits, or lesions, which do not fulfil RECIST v1.1 criteria for measurabledisease) for solid tumours

3. NUC-7738 + pembrolizumab cohort only (Phase II): Histologically confirmed diagnosisof metastatic cutaneous melanoma with measurable disease as per RECIST v1.1criteria. Must have primary or secondary resistance to checkpoint inhibitors:

• Confirmed disease progression on/after an approved anti-PD-1 agent with or withoutan anti-CTLA4 agent, administered either as a combination regimen (e.g., nivolumab +ipilimumab) or in sequence

• Treatment with prior anti-PD-1 therapy must have continued for a minimum of 8weeks

• Patients who are not candidates for treatment with anti-CTLA4 therapy (in theInvestigator's opinion) are eligible

• Patients with documented BRAF V600 mutation status should have received priorBRAF-directed therapy (with or without a MEK inhibitor), unless not consideredclinically indicated (in the Investigator's opinion)

4. Lymphoma cohort only (Phase II): Relapsed refractory lymphoma (high grade and lowgrade B-NHL, Hodgkin's Lymphoma and T-cell lymphomas), which is not amenable tostandard of care, is refractory to standard of care or for which no standard of careexists. Patients must have bi-dimensionally measurable disease as per Cheson et al, 2007 criteria for lymphoma.

5. For solid tumours in single-agent Phase II cohorts only: patients should havereceived no more than 3 prior lines of treatment for metastatic disease.

6. Age ≥18 years (no upper age limit)

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

8. Life expectancy of ≥12 weeks

9. Adequate bone marrow, liver, and renal function

10. Ability to comply with protocol requirements

11. Female patients of child-bearing potential must have a negative serum pregnancy testwithin 3 days prior to the first NUC-7738 administration. All patients ofchild-bearing potential must agree to practice true abstinence or to use two formsof contraception, one of which must be a highly effective method of contraception,from the time of screening until 6 months after the last dose of study medication.

12. Phase I and Phase II dose-confirmation cohorts only: Patient must be willing toundergo a new tumour biopsy at Screening and during therapy on the study. Biopsiesare mandatory for patient inclusion, except where taking a biopsy would beassociated with unacceptable clinical risk due to the location of the disease. Suchpatients may be discussed on a case-by-case basis with the study Medical Monitor todetermine their eligibility. A prior (archival) biopsy that is less than 3 monthsold may be substituted for a fresh tumour biopsy at Screening with agreement fromthe Medical Monitor.

13. Patients must have been advised to take measures to avoid or minimise exposure ofthe skin and eyes to UV light, including avoiding sunbathing and visits to thesolarium, for the duration of study participation and for a period of 4 weeksfollowing the last dose of study medication.

Exclusion Criteria:

The following exclusion criteria apply to all patients. Please also refer to additional exclusion criteria for the NUC-7738 + pembrolizumab cohort below.

1. History of allergic reaction fo any of the components of NUC-7738

2. Symptomatic central nervous system or leptomeningeal metastases

3. Chemotherapy, radiotherapy (other than a short cycle of palliative radiotherapy forbone pain), immunotherapy, or exposure to another investigational agent within 28days (for biological agents decision on washout period will be made on a case bybase basis) of first administration of the IMP:

4. For nitrosoureas and mitomycin C within 6 weeks of first administration ofNUC-7738

5. For hormone therapy within 14 days of first administration of NUC-7738

6. Corticosteroid treatment is allowed during the screening period but should beweaned to a dose of 10 mg prednisolone (or steroids equivalent) by Cycle 1 Day

8. Phase II only; prior treatment with CAR-T cells

9. Prior toxicities from anti-cancer agents or radiotherapy, which have not regressedto Grade ≤1 severity (NCI-CTCAE v5.0), excluding neuropathy, ototoxicity andalopecia (which are excluded if ≥Grade 3).

10. Presence of any uncontrolled concomitant illness, serious illness, medicalconditions, or other medical history, including laboratory results, which, in theInvestigator's opinion, would be likely to interfere with their participation in thestudy, or with the interpretation of results, including the following:

11. Congestive heart failure (New York Heart Association Class III or Class IV)

12. Myocardial infarction within 6 months of the first dose of study medication

13. Unstable or poorly controlled angina pectoris

14. Complete left bundle branch, bifascicular block or other clinically significantabnormal electrocardiogram finding

15. A history of or current risk factor for Torsades de Point (e.g., heart failure,hypokalaemia, or a family history of long QT syndrome)

16. A history of, or current diagnosis of, interstitial pneumonitis or pulmonaryfibrosis

17. Known human immunodeficiency virus positive or known active hepatitis B or C.Presence of an active bacterial or viral infection including Herpes zoster orchicken pox

18. Any condition (e.g., known or suspected poor compliance, psychological instability,geographical location etc.) that, in the judgment of the Investigator, may affectthe patient's ability to sign the informed consent and undergo study procedures

19. Currently pregnant, lactating or breastfeeding

20. QTc interval >450 milliseconds for males and >470 milliseconds for females

21. Concomitant use of drugs known to prolong QT/QTc interval

22. Concomitant use of strong CYP3A4 inducers or strong CYP3A4 inhibitors. The use ofstrong CYP3A4 inducers within 2 weeks of first receipt of study drug or the use ofstrong CYP3A4 inhibitors within 1 week of first receipt of study drug is alsoexcluded.

23. Have received a live vaccination within four weeks of first planned dose of studymedication.

NUC-7738 + pembrolizumab cohort only

1. Any history of hypersensitivity or current contra-indication to the components ofpembrolizumab (L-histidine, polysorbate 80, sucrose, sodium hydroxide, hydrochloricacid)

2. Current contra-indication to immunotherapy with checkpoint inhibitors.

3. Systemic steroid therapy or any immunosuppressive therapy (≥10 mg/day prednisone orequivalent).

4. Known neutralising antibodies against checkpoint inhibitors.

5. Patients previously exposed to checkpoint inhibitors who are not adequately treatedfor skin rash or have no replacement therapy for endocrinopathies.

6. Any prior toxicity attributed to checkpoint inhibitors that resulted indiscontinuation of therapy

7. Active autoimmune disease or a documented history of autoimmune disease, includingulcerative colitis and Crohn's disease or any condition that requires systemicsteroids.