NUC-3373 in Advanced Solid Tumours

A two-part, phase I open label, dose escalation and expansion study to assess safety, pharmacokinetics and clinical activity of NUC-3373, a nucleotide analogue, in participants with advanced solid tumours.

This is a two-part, Phase I dose escalation study of NUC-3373 (a pyrimidine nucleotide analogue) as a single agent, administered weekly or fortnightly as an I.V. (intravenous) infusion.

In both parts participants will undergo evaluations of the safety, PK (pharmacokinetics), PD (pharmacodynamics) and anti-tumour efficacy of NUC-3373

• Participants may continue to receive NUC-3373 until disease progression or unacceptable toxicity occurs.

Part 1: Establish the RP2D (recommended phase two dose) and assess the safety and tolerability for single agent NUC-3373 administered as an I.V. infusion on day 1, 8, 15, 22 of a 28-day cycle. Participants can remain on study and receive treatment until disease progression or unacceptable toxicity occurs. The RP2D will be determined by dose escalation with sequential participants receiving increasing doses of NUC-3373 in a standard '3 + 3' cohort design.

Part 2: Establish the RP2D and assess the safety and tolerability for single agent NUC-3373 administered as a fortnightly I.V. infusion on day 1 and 15 of a 28-day cycle. Participants can remain on study and receive treatment until disease progression or unacceptable toxicity occurs. The RP2D will be determined by dose escalation with sequential participants receiving increasing doses of NUC-3373 in a standard '3 + 3' cohort design.

Finally, to assess preliminary efficacy signals and further characterise the safety profile, expansion cohorts of up to 20 additional participants per cohort will receive the RP2D of NUC-3373 as determined in Part 1 and Part 2 of the study. Participants can remain on study and receive treatment until disease progression or unacceptable toxicity occurs.

Eligibility Criteria:
Inclusion Criteria:

1. Provision of signed written informed consent.
2. Diagnosis: Histologically confirmed diagnosis of solid tumour, which is not amenable to standard chemotherapy, is refractory to standard chemotherapy or for which no standard chemotherapy exists.
3. Age ≥ 18 years.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
5. Life expectancy of ≥ 12 weeks.
6. Participants must have measurable disease per RECIST criteria and/or evaluable disease (evaluable: cytologically or radiologically detectable disease such as ascites, peritoneal deposits, or lesions which do not fulfil RECIST criteria for measurable disease).
7. Adequate bone marrow function as defined by: WBC of ≥ 3 x109/L, ANC of ≥ 1.5 x 109/L, platelet count of ≥ 100 x 109/L, and haemoglobin of ≥ 9g/dL.
8. Adequate liver function, as determined by: Serum total bilirubin ≤1.5 x ULN, AST and ALT ≤ 2.5 x ULN.
9. Adequate renal function as defined by serum creatinine within ≤ 1.5 x ULN upper limits of normal or calculated clearance ≥50 ml/min/1.73 m2. If using creatinine clearance, actual body weight should be used for calculating creatinine clearance (using the Cockcroft-Gault formula). For subjects with a Body Mass Index (BMI) \>30 kg/m2, lean body weight should be used instead
10. Left Ventricular Ejection Fraction (LVEF) ≥50% on echocardiogram
11. Ability to comply with protocol requirements.
12. Female participants of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test prior to the first scheduled IMP administration at Cycle 1 Day 1. .

Exclusion Criteria:

1. History of allergic reactions attributed to previous 5-FU or capecitabine treatment.
2. History of allergic reactions to any of the components of the diluent solutions supplied with NUC-3373.
3. Symptomatic CNS or leptomeningeal metastases.
4. Participants with a history of myocardial infarction within the last 5 years or with significant cardiac arrhythmias requiring medication or pacemaker.
5. Prior chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy for bone pain), immunotherapy or any other anticancer agent within 28 days of first administration of the IMP.

   * For nitrosoureas and mitomycin C within 6 weeks of first administration of IMP.
   * For hormone or biological therapy within 14 days of first administration of IMP.
6. Prior toxicities from chemotherapy or radiotherapy which have not regressed to Grade ≤ 1 severity (NCI-CTCAE version 4.0) apart from renal function (provided inclusion criteria 9 is met), neuropathy and alopecia.
7. Another active cancer excluding basal cell carcinoma or intraepithelial neoplasia (CIN/cervical in situ or melanoma in situ).
8. Participants with uncontrolled concomitant illness, active infection requiring i.v. antibiotics, or uncontrolled infections, or a fever \>38.5°C on the day of scheduled dosing.
9. Participants with serious illnesses, medical conditions, or other medical history, including laboratory results, which, in the CI or delegates opinion would be likely to interfere with a participant's participation in the study, or with the interpretation of the results.
10. Known HIV or known active Hepatitis B or C.
11. Any condition (e.g. known or suspected poor compliance, psychological instability, geographical location, etc.) that, in the judgment of the CI or delegates may affect the participant's ability to sign the informed consent and undergo study procedures.
12. All men or women of reproductive potential, unless using at least two contraceptive precautions, one of which must be from the list below, the other must be a condom\*1 or abstaining from sexual intercourse, until six months after treatment has ended:

    * Combined (oestrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation: either oral, intravaginal or transdermal.
    * Progesterone-only hormonal contraception associated with inhibition of ovulation: either oral, injectable or implantable.
    * Intra-uterine device (IUD)
    * Intra-uterine hormone-releasing system (IUS)
    * Bilateral tubal occlusion
    * Vasectomised partner\*2
    * Sexual abstinence\*3
13. Participants who are currently breastfeeding.