NUC-3373 in Combination With Other Agents in Patients With Advanced Solid Tumours

Inclusion Criteria (all modules):

1. Provision of written informed consent.

2. Confirmed diagnosis of one of the protocol-specified tumour types (refer to therelevant module for specific criteria).

3. Age ≥18 years.

4. Minimum life expectancy of ≥12 weeks.

5. Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1.

6. Measurable disease as defined by RECIST v1.1.

7. Adequate bone marrow function as defined by absolute neutrophil count (ANC) ≥1.5×109/L, platelet count ≥100×109/L (with no evidence of bleeding), andhaemoglobin ≥9 g/dL.

8. Adequate liver function (refer to the relevant module for specific criteria).

9. Adequate renal function assessed as serum creatinine <1.5× upper limit of normal (ULN) and glomerular filtration rate ≥50 mL/min (calculated by the Cockcroft-Gaultmethod).

10. Serum albumin ≥3 g/dL.

11. For the module in which the patient will participate, there are nocontra-indications to receiving the approved partner combination drugs.

12. Ability to comply with protocol requirements.

13. Female patients of child-bearing potential must have a negative pregnancy testwithin 7 days prior to the first study drug administration. This criterion does notapply to patients who have had a previous hysterectomy or bilateral oophorectomy.Male patients and female patients of child-bearing potential must agree to practicetrue abstinence or to use two forms of contraception, one of which must be highlyeffective. These forms of contraception must be used from the time of signingconsent, throughout the treatment period, and for 6 months following the last doseof any study medication. Oral or injectable contraceptive agents cannot be the solemethod of contraception.

14. Patients must have been advised to take measures to avoid or minimize exposure toultraviolet (UV) light for the duration of study participation and for a period of 4weeks following the last dose of study medication.

Additional Module 1 Inclusion Criteria:

1. Confirmed diagnosis of a solid tumour, with evidence of locallyadvanced/unresectable or metastatic disease, for which pembrolizumab treatment wouldbe appropriate (e.g., melanoma, classical Hodgkin lymphoma, NSCLC, renal cellcarcinoma (RCC), urothelial carcinoma, head and neck squamous cell carcinoma (HNSCC), cutaneous squamous cell carcinoma (cSCC), oesophageal carcinoma,microsatellite instability (MSI) high colorectal (CRC), gastric cancer, triplenegative breast cancer (TNBC), and endometrial carcinoma).

2. Must have progressed on ≤2 prior lines of therapy for advanced/metastatic disease,that may have included 1 prior line of an immunotherapy-containing regimen (eithermonotherapy or in combination with chemotherapy). Patients who have not progressedbut where addition of NUC-3373 + LV to standard pembrolizumab monotherapy may beappropriate are also eligible (e.g., patients who could not tolerate post-IOstandard of care therapy).

3. Patient must be willing to undergo a new tumour biopsy at Screening and duringtherapy on the study. Biopsies are mandatory for patient inclusion, except wheretaking a biopsy would be associated with unacceptable clinical risk due to thelocation of the disease. A prior (archival) biopsy that is less than 6 months old (from the date of Cycle 1Day 1; C1D1) may be substituted for a fresh tumour biopsyat Screening.

4. Adequate liver function, as defined by serum total bilirubin ≤1.5×ULN, aspartateaminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN (or ≤5×ULN ifliver metastases are present).

Additional Module 2 Inclusion Criteria:

1. Confirmed diagnosis of NSCLC (any histology) or pleural mesothelioma (any histology)with evidence of locally advanced/unresectable or metastatic disease.

2. Must have progressed on, or were unable to tolerate, 1 or 2 prior lines of cytotoxicchemotherapy-containing standard of care regimens for advanced/metastatic disease (not including neoadjuvant or adjuvant therapy). Additional prior lines of treatmentwith targeted agents or immunotherapy are allowed as long as they were not given incombination with cytotoxic chemotherapy. Prior regimens in which one drug issubstituted for another due to toxicity count as 1 line of treatment. Priortreatment with docetaxel for metastatic disease is not allowed.

3. Adequate liver function, as defined by serum total bilirubin <ULN, AST and ALT ≤2.5×ULN (or ≤5×ULN if liver metastases are present). In the event of concomitantlyincreased alkaline phosphatase (ALP) values >2.5×ULN, AST and ALT must be <1.5×ULN.

Exclusion Criteria (all modules):

1. History of hypersensitivity or current contra-indications to 5-fluorouracil (5-FU),floxuridine (FUDR), capecitabine (refer to latest package inserts), or thecomponents of the NUC-3373 drug product formulation (super refined polysorbate 80 [SRP80], dimethylacetamide [DMA]).

2. Symptomatic central nervous system or leptomeningeal metastases.

3. Symptomatic ascites, ascites currently requiring drainage procedures or ascitesrequiring drainage over the 3 months prior to date of first dose of study drug.

4. Chemotherapy, hormonal therapy, radiotherapy (other than a short cycle of palliativeradiotherapy, e.g., for bone pain*), immunotherapy, biological agents, or exposureto another investigational agent within 21 days (or four times the half-life formolecular targeted agents, whichever is shorter) of first administration of studytreatment:

5. For nitrosoureas and mitomycin C within 6 weeks of first administration ofNUC-3373

6. Corticosteroid treatment is allowed during screening but should be weaned to adose of 10 mg prednisolone (or steroid equivalent) by Cycle 1 Day 1 *Palliative radiotherapy during participation in the study is permitted, butshould not be concurrent with study treatment and recovery should be allowed toprevent overlapping toxicity. It should not include a target lesion.

7. Residual toxicities from prior chemotherapy, immunotherapy or radiotherapy whichhave not regressed to Grade ≤1 severity (Common Terminology Criteria for AdverseEvents (CTCAE) v5.0), except for alopecia, peripheral neuropathy and ototoxicity (which are excluded if ≥Grade 3).

8. Uncontrolled concurrent cancer other than the indication under investigation.Patients with a concurrent cancer whose natural history or treatment does not havethe potential to interfere with safety or efficacy assessment are eligible.

9. Presence of an active bacterial or viral infection (including severe acuterespiratory syndrome coronavirus 2 (SARS-CoV- 2), Herpes Zoster or chicken pox), orknown active hepatitis B or C.

10. Presence of any uncontrolled concurrent serious illness, medical condition or othermedical history, including laboratory results, which, in the Investigator's opinion,would be likely to interfere with the patient's ability to participate in the studyor with the interpretation of the results, including any of the following:

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

12. Clinically significant coronary heart disease or myocardial infarction within 6months of the first dose of study medication or high risk of uncontrolledarrythmia

13. Unstable or poorly controlled angina pectoris

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

15. Corrected QT (QTc) interval >470 milliseconds

16. History of or current risk factor for torsade de pointes (e.g., heart failure,hypokalaemia, or a family history of long QT syndrome)

17. History of severe skin reactions

18. History of severe ocular disorders

19. Interstitial pneumonitis or pulmonary fibrosis

20. 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.

21. Currently pregnant, lactating or breastfeeding.

22. Required concomitant use of drugs known to prolong QT/QTc interval.

23. Required concomitant use of strong CYP3A4 inducers or strong CYP3A4 inhibitors. Theuse of strong CYP3A4 inducers within 2 weeks of first receipt of study drug or theuse of strong CYP3A4 inhibitors within 1 week of first receipt of study drug is alsoexcluded.

24. Use of live attenuated vaccines against infectious diseases (e.g., measles mumpsrubella [MMR combined vaccines], Rotavirus, Chickenpox, yellow fever) within 4 weeksof initiation of study treatment.

25. Known dihydropyrimidine dehydrogenase (DPD) or thymidine phosphorylase (TYMP)mutations associated with toxicity to fluoropyrimidines.

26. Full-dose anti-coagulation treatment is prohibited. Use of warfarin and other typesof long-acting anti-coagulants (such as phenprocoumon and anti-Xa inhibitors with ahalf-life of >12 hours) is prohibited within 4 weeks of the first dose of studytreatment. Patients requiring low dose anti-coagulant treatment should switch to lowmolecular weight heparin or anti-Xa inhibitors with a half-life of ≤12 hours.

Additional Module 1 Exclusion Criteria:

1. Prior history of hypersensitivity or current contra-indication to immunotherapy withcheckpoint inhibitors.

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

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

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

5. Known neutralising antibodies against checkpoint inhibitors.

6. Patients who have received >2 prior lines of therapy or who have received >1 priorline of an immunotherapy-containing regimen for advanced/metastatic disease.

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

8. Congenital or acquired immunodeficiency (e.g., serious active infection with humanimmunodeficiency virus (HIV)).

9. Patients with a history of drug induced pneumonitis or current pneumonitis.

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

Additional Module 2 Exclusion Criteria:

1. Prior history of hypersensitivity or current contra-indication to docetaxel,polysorbate 80, ethanol (anhydrous) or citric acid.

2. Total serum bilirubin >ULN and/or AST and ALT ≥1.5×ULN together with concomitantlyincreased ALP values >2.5×ULN.

3. Patients who have received >2 prior lines of cytotoxic chemotherapy-containingregimens for advanced/metastatic disease.

4. Patients who have received prior treatment with docetaxel for advanced/metastaticdisease.

5. Congenital or acquired immunodeficiency (e.g., serious active infection with HIV).Patients with HIV who are healthy and have a low risk of acquired immunodeficiencysyndrome (AIDS)-related outcomes are eligible.