A Safety, Pharmacokinetic and Clinical Activity Study of NUC-7738 in Patients With Advanced Solid Tumours and Lymphoma

This is a Phase I/II, dose-escalation and expansion study of NUC-7738 administered by intravenous infusion as a monotherapy and in combination with pembrolizumab.

In Phase I, NUC-7738 monotherapy is evaluated across two administration schedules (weekly or fortnightly) in a dose-escalation design in patients with advanced solid tumours. The main objectives are to assess the safety and tolerability of NUC-7738, in addition to establishing the Maximum Tolerated Dose (MTD) and dose administration schedule of NUC-7738 for further exploration in the Phase II part of the study.

In Phase II, the selected dose and designated dosing schedule will be further evaluated in dose-confirmation expansion cohorts enrolling a total of approximately 40 additional patients with advanced solid tumours. Based on emerging data, approximately 6 patients with cutaneous melanoma will be enrolled to these expansion cohorts and will receive NUC-7738 monotherapy. A further cohort will assess NUC-7738 in combination with pembrolizumab in approximately 6-12 patients with cutaneous melanoma. Based on efficacy signals observed in the initial melanoma combination cohort, a further expansion cohort will be initiated to expand to a total of 40 patients to allow a powered analysis. In addition, 12 patients with lymphoma (with potential expansion to a total of 25 patients) may be enrolled to receive NUC-7738 monotherapy.


Eligibility Criteria:
Inclusion Criteria:

1. Provision of signed written informed consent
2. Solid tumour cohorts only (Phase I and Phase II; excluding NUC-7738 + pembrolizumab cohort): Histologically confirmed diagnosis of an advanced solid tumour with measurable disease as per RECIST v1.1 criteria and/or evaluable disease (evaluable: cytologically or radiologically detectable disease such as ascites, peritoneal deposits, or lesions, which do not fulfil RECIST v1.1 criteria for measurable disease) for solid tumours
3. NUC-7738 + pembrolizumab cohort only (Phase II): Histologically confirmed diagnosis of metastatic cutaneous melanoma with measurable disease as per RECIST v1.1 criteria. Must have primary or secondary resistance to checkpoint inhibitors:

   • Confirmed disease progression on/after an approved anti-PD-1 agent with or without an anti-CTLA4 agent, administered either as a combination regimen (e.g., nivolumab + ipilimumab) or in sequence
   * Treatment with prior anti-PD-1 therapy must have continued for a minimum of 8 weeks
   * Patients who are not candidates for treatment with anti-CTLA4 therapy (in the Investigator's opinion) are eligible
   * Patients with documented BRAF V600 mutation status should have received prior BRAF-directed therapy (with or without a MEK inhibitor), unless not considered clinically indicated (in the Investigator's opinion)
4. Lymphoma cohort only (Phase II): Relapsed refractory lymphoma (high grade and low grade B-NHL, Hodgkin's Lymphoma and T-cell lymphomas), which is not amenable to standard of care, is refractory to standard of care or for which no standard of care exists. Patients must have bi-dimensionally measurable disease as per Cheson et al, 2007 criteria for lymphoma.
5. For solid tumours in single-agent Phase II cohorts only: patients should have received no more than 3 prior lines of treatment for metastatic disease.
6. Age ≥18 years (no upper age limit)
7. Eastern Cooperative Oncology Group performance status of 0 or 1
8. Life expectancy of ≥12 weeks
9. Adequate bone marrow, liver, and renal function
10. Ability to comply with protocol requirements
11. Female patients of child-bearing potential must have a negative serum pregnancy test within 3 days prior to the first NUC-7738 administration. All patients of child-bearing potential must agree to practice true abstinence or to use two forms of contraception, one of which must be a highly effective method of contraception, from the time of screening until 6 months after the last dose of study medication.
12. Phase I and Phase II dose-confirmation cohorts only: Patient must be willing to undergo a new tumour biopsy at Screening and during therapy on the study. Biopsies are mandatory for patient inclusion, except where taking a biopsy would be associated with unacceptable clinical risk due to the location of the disease. Such patients may be discussed on a case-by-case basis with the study Medical Monitor to determine their eligibility. A prior (archival) biopsy that is less than 3 months old may be substituted for a fresh tumour biopsy at Screening with agreement from the Medical Monitor.
13. Patients must have been advised to take measures to avoid or minimise exposure of the skin and eyes to UV light, including avoiding sunbathing and visits to the solarium, for the duration of study participation and for a period of 4 weeks following the last dose of study medication.

Exclusion Criteria:

The following exclusion criteria apply to all patients. Please also refer to additional exclusion criteria for the NUC-7738 + pembrolizumab cohort below.

1. History of allergic reaction fo any of the components of NUC-7738
2. Symptomatic central nervous system or leptomeningeal metastases
3. Chemotherapy, radiotherapy (other than a short cycle of palliative radiotherapy for bone pain), immunotherapy, or exposure to another investigational agent within 28 days (for biological agents decision on washout period will be made on a case by base basis) of first administration of the IMP:

   1. For nitrosoureas and mitomycin C within 6 weeks of first administration of NUC-7738
   2. For hormone therapy within 14 days of first administration of NUC-7738
   3. Corticosteroid treatment is allowed during the screening period but should be weaned to a dose of 10 mg prednisolone (or steroids equivalent) by Cycle 1 Day 1.
4. Phase II only; prior treatment with CAR-T cells
5. Prior toxicities from anti-cancer agents or radiotherapy, which have not regressed to Grade ≤1 severity (NCI-CTCAE v5.0), excluding neuropathy, ototoxicity and alopecia (which are excluded if ≥Grade 3).
6. Presence of any uncontrolled concomitant illness, serious illness, medical conditions, 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 results, including the following:

   1. Congestive heart failure (New York Heart Association Class III or Class IV)
   2. Myocardial infarction within 6 months of the first dose of study medication
   3. Unstable or poorly controlled angina pectoris
   4. Complete left bundle branch, bifascicular block or other clinically significant abnormal electrocardiogram finding
   5. A history of or current risk factor for Torsades de Point (e.g., heart failure, hypokalaemia, or a family history of long QT syndrome)
   6. A history of, or current diagnosis of, interstitial pneumonitis or pulmonary fibrosis
7. Known human immunodeficiency virus positive or known active hepatitis B or C. Presence of an active bacterial or viral infection including Herpes zoster or chicken pox
8. 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
9. Currently pregnant, lactating or breastfeeding
10. QTc interval \>450 milliseconds for males and \>470 milliseconds for females
11. Concomitant use of drugs known to prolong QT/QTc interval
12. Concomitant use of strong CYP3A4 inducers or strong CYP3A4 inhibitors. The use of strong CYP3A4 inducers within 2 weeks of first receipt of study drug or the use of strong CYP3A4 inhibitors within 1 week of first receipt of study drug is also excluded.
13. Have received a live vaccination within four weeks of first planned dose of study medication.

NUC-7738 + pembrolizumab cohort only

1. Any history of hypersensitivity or current contra-indication to the components of pembrolizumab (L-histidine, polysorbate 80, sucrose, sodium hydroxide, hydrochloric acid)
2. Current contra-indication to immunotherapy with checkpoint inhibitors.
3. Systemic steroid therapy or any immunosuppressive therapy (≥10 mg/day prednisone or equivalent).
4. Known neutralising antibodies against checkpoint inhibitors.
5. Patients previously exposed to checkpoint inhibitors who are not adequately treated for skin rash or have no replacement therapy for endocrinopathies.
6. Any prior toxicity attributed to checkpoint inhibitors that resulted in discontinuation of therapy
7. Active autoimmune disease or a documented history of autoimmune disease, including ulcerative colitis and Crohn's disease or any condition that requires systemic steroids.