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

          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 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 fluoropyrimide-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. 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 fluoropyrimide-containing
             regimen

          3. Patients in Part 2 or 3 due to receive NUFOX should be suitable for re-challenge with
             an oxaliplatin-based regimen

          4. Patients in Part 2 or 3 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 for bone
             pain), immunotherapy or exposure to another investigational agent within 28 days (or
             five times half-life for a biological 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. Irinotecan cohorts: use of strong CYP3A4 inducers within 2 weeks of first dose of
             study drug or use of strong CYP3A4 or UGT1A1 inhibitors within 1 week of first dose of
             study drug

         16. Has received a live vaccination within four weeks of first planned dose of study
             medication

         17. Known DPD or TYMP mutations associated with toxicity to fluoropyrimidines

         18. 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