This is a three-part study of NUC-3373 administered by intravenous (IV) infusion across two administration schedules, either as monotherapy or as part of various combinations with agents commonly used to treat CRC (leucovorin, oxaliplatin, irinotecan, bevacizumab, cetuximab and panitumumab). The primary objective is to identify a recommended dose and schedule for NUC-3373 when combined with these agents.

Inclusion Criteria:

All patients

1. Provision of written informed consent
2. Have histological confirmation of CRC with evidence of locally advanced/unresectable or metastatic disease
3. Age ≥18 years
4. Life expectancy of ≥12 weeks
5. ECOG Performance status 0 or 1
6. Measurable disease as defined by RECIST v1.1
7. Known RAS and BRAF status. Patients with wild-type KRAS tumours who are to be enrolled to a cohort that does not contain an EGFR pathway inhibitor (Arms 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d and 3e) must have received prior treatment with an EGFR inhibitor, unless this was not standard of care according to relevant region-specific treatment recommendations. Patients with BRAF V600E mutant tumours should have received prior treatment with encorafenib in combination with an EGFR inhibitor, unless this was not standard of care according to relevant region-specific treatment recommendations
8. Adequate bone marrow function as defined by: ANC ≥1.5×10^9/L, platelet count ≥100×10^9/L (with no evidence of bleeding), and haemoglobin ≥9 g/dL
9. Adequate liver function as defined by serum total bilirubin ≤1.5×ULN, AST and ALT ≤2.5×ULN (or ≤5×ULN if liver metastases present)
10. Adequate renal function assessed as serum creatinine <1.5×ULN or glomerular filtration rate ≥50 mL/min. This criterion does not apply to Arm 1d.
11. Serum albumin ≥3 g/dL
12. For the cohort in which the patient will participate, there are no contra-indications to receiving the approved partner combination drugs
13. Ability to comply with protocol requirements
14. Female patients of child-bearing potential must have a negative serum pregnancy test within 7 days prior to the first study drug administration. This criterion does not apply to patients who have had a previous hysterectomy or bilateral oophorectomy. Male patients and female patients of child-bearing potential must agree to practice true abstinence or to use two highly effective forms of contraception, one of which must be a barrier method.
15. Patients must have been advised to take measures to avoid or minimise exposure to UV light for the duration of study participation and for a period of 4 weeks following the last dose of study medication
16. Male patients receiving oxaliplatin must have been offered advice on and/or sought counselling for conservation of sperm prior to the first dose of study medication

>3rd-line patients

1. Received at least two prior lines of therapy for locally advanced or metastatic CRC, including one fluoropyrimidine plus oxaliplatin and one fluoropyrimidine plus irinotecan containing regimen. Previous treatment with SoC regimens in combination with molecular targeted therapies is permitted and patients who received FOLFOXIRI-based regimens in 1st-/2nd-line settings may be included.
2. Patients due to receive NUFOX should be suitable for re-challenge with an oxaliplatin-based regimen
3. Patients due to receive NUFIRI should be suitable for re-challenge with an irinotecan-based therapy

2nd-/3rd-line patients

1. Received at least one but no more than two prior lines of fluoropyrimidine-containing therapy in combination with oxaliplatin and/or irinotecan for locally advanced or metastatic CRC. Previous treatment with SoC regimens in combination with molecular targeted therapies is permitted and patients who received FOLFOXIRI-based regimens in 1st-/2nd-line settings may be included. 3rd-line patients enrolled to Arms 2c and 2d must have received prior bevacizumab treatment, unless ineligible or unless bevacizumab was not standard of care according to relevant region-specific treatment recommendations
2. Patients in Part 2 due to receive NUFOX should be suitable for re-challenge with an oxaliplatin-based regimen
3. Patients in Part 2 due to receive NUFIRI should be suitable for re-challenge with an irinotecan-based regimen

Combination chemotherapy ineligible patients

1. May have received one prior fluoropyrimidine-containing regimen for locally advanced or metastatic CRC
2. Ineligible to receive combination therapy for locally advanced or metastatic CRC
3. Creatinine clearance >30mL/min

Rapid progressors

1. Received no more than two prior lines of fluoropyrimidine-containing therapy in combination with oxaliplatin and/or irinotecan for locally advanced or metastatic CRC. Previous treatment with SoC regimens in combination with molecular targeted therapies is permitted and patients who received FOLFOXIRI-based regimens in 1st-/2nd-line settings may be included.
2. Have had tumour progression ≤3 months of starting the last fluoropyrimidine-containing regimen
3. Patients due to receive NUFOX should be suitable for re-challenge with an oxaliplatin-based regimen
4. Patients due to receive NUFIRI should be suitable for re-challenge with an irinotecan-based regimen

2nd-line patients

1. Received one prior line of fluoropyrimidine-containing therapy in combination with oxaliplatin and/or irinotecan for locally advanced or metastatic CRC. Previous treatment with SoC regimens in combination with molecular targeted therapies is permitted and patients who received triplet chemotherapy based regimens is allowed.

Maintenance patients

1. Received at least 12 weeks of 1st-line SoC therapy for locally advanced or metastatic CRC and achieved at least stable disease
2. Eligible for maintenance therapy

Exclusion Criteria:

All patients

1. Prior history of hypersensitivity or current contra-indications to 5-FU or capecitabine
2. Prior history of hypersensitivity or current contra-indications to any of the combination agents required for the study arm to which the patient is assigned
3. History of allergic reactions attributed to the components of the NUC-3373 drug product formulation
4. Symptomatic CNS or leptomeningeal metastases
5. Symptomatic ascites, ascites currently requiring drainage procedures or ascites requiring drainage over the prior 3 months
6. Chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy [e.g. for bone pain]), immunotherapy or exposure to another investigational agent within 28 days (or five times half-life for a biological or molecular targeted agent or three times the half-life for an immunotherapy agent) of first receipt of study drug
7. Residual toxicities from prior chemotherapy or radiotherapy, which have not regressed to Grade ≤1 severity (CTCAE v5.0) except for alopecia. In cohorts not containing oxaliplatin, residual Grade 2 neuropathy is allowed.
8. History of another malignancy diagnosed within the past 5 years, with the exception of adequately treated non-melanoma skin cancer curatively treated carcinoma in situ of the cervix, surgically excised or potentially curatively treated ductal carcinoma in situ of the breast, or low grade prostate cancer or patients after prostatectomy not requiring treatment. Patients with previous invasive cancers are eligible if treatment was completed more than 3 years prior to initiating the current study treatment and there is no evidence of recurrence.
9. Presence of active bacterial or viral infection (including SARS-CoV-2, Herpes Zoster or chicken pox), known HIV positive or known active hepatitis B or C
10. Presence of any uncontrolled concurrent serious illness, medical condition or other medical history, including laboratory results, which, in the Investigator's opinion, would be likely to interfere with their participation in the study, or with the interpretation of the results
11. Any condition (e.g. known or suspected poor compliance, psychological instability, geographical location) that, in the judgment of the Investigator, may affect the patient's ability to sign the informed consent and undergo study procedures
12. Currently pregnant, lactating or breastfeeding
13. QTc interval >450 milliseconds for males and >470 milliseconds for females
14. Required concomitant use of drugs known to prolong QT/QTc interval
15. Required concomitant use of strong CYP3A4 inducers or strong CYP3A4 inhibitors, or use of strong CYP3A4 inducers within 2 weeks of first receipt of study drug or use of strong CYP3A4 inhibitors within 1 week of first receipt of study drug
16. For patients receiving irinotecan: Use of strong UGT1A1 inhibitors within 1 week of first receipt of study drug
17. Has received a live vaccination within four weeks of first planned dose of study medication
18. Known DPD or TYMP mutations associated with toxicity to fluoropyrimidines
19. Use of warfarin and other types of long acting anti-coagulants is prohibited within 4 weeks of the first dose of study treatment

Patients receiving bevacizumab

1. Patients with a history of haemoptysis (≥1/2 tsp of red blood)
2. Wound healing complications or surgery within 28 days of starting bevacizumab
3. Severe chronic wounds, ulcers or bone fracture
4. Arterial thromboembolic events or haemorrhage within 6 months prior to study entry (except for tumour bleeding surgically treated by tumour resection)
5. Bleeding diatheses or coagulopathy
6. Receiving full-dose anti-coagulation treatment
7. Uncontrolled hypertension
8. Clinically significant coronary heart disease or myocardial infarction within the last 12 months or high risk of uncontrolled arrhythmia
9. Severe proteinuria
10. Acute or subacute ileus, chronic inflammatory bowel disease or chronic diarrhoea
11. Any contraindications present in the bevacizumab Prescribing Information

Patients receiving cetuximab or panitumumab

1. Clinically significant coronary heart disease or myocardial infarction within the last 12 months or high risk of uncontrolled arrhythmia
2. Acute or subacute ileus, chronic inflammatory bowel disease or chronic diarrhoea
3. Hypomagnesaemia or hypokalaemia not controlled by oral therapy
4. Any contraindications present in the cetuximab or panitumumab Prescribing Information