A Safety Study of NUC-3373 in Combination With Standard Agents Used in Colorectal Cancer Treatment

Inclusion Criteria:

1. Provision of signed written informed consent.

2. Have histological confirmation of locally advanced/unresectable or metastatic
colorectal cancer, with evidence of disease recurrence.

3. Have relapsed on or after at least at least two prior lines of therapy for locally
advanced/unresectable or metastatic colorectal cancer. One prior line of therapy must
be an oxaliplatin + 5-FU containing regimen and one prior line of therapy must be an
irinotecan + 5-FU containing regimen.

4. Age ≥18 years.

5. ECOG Performance status 0 or 1.

6. Measurable disease as defined by RECIST.

Exclusion Criteria:

1. Prior history of hypersensitivity or current contraindications to 5-FU or capecitabine
or the combination agent to be used.

2. History of allergic reactions attributed to the components of the diluents used with
NUC-3373.

3. Symptomatic CNS or leptomeningeal metastases.

4. Prior chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy
for bone pain), treatment with a VEGF inhibitor, EGF inhibitor or immunotherapy within
21 days of first receipt of study drug.

5. Residual toxicities from chemotherapy or radiotherapy, which have not regressed to
Grade ≤1 severity (CTCAE v4.03), except for alopecia. In Cohorts 1a, 1b, 3a, and 3b,
residual Grade 2 neuropathy is allowed.

6. 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 or ductal carcinoma in situ (DCIS) of the breast. Patients with previous
invasive cancers are eligible if treatment was completed more than 5 years prior to
initiating the current study treatment, and the patient has had no evidence of
recurrence since then.

7. Presence of active bacterial or viral infection including Herpes Zoster or chicken
pox.

8. Presence of any serious uncontrolled concomitant illness, 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.

9. Known HIV positive or known active hepatitis B or C.

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

11. Currently pregnant, lactating or breastfeeding.

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

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

14. Have received a live vaccination within four weeks of first planned dose of study
medication.