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

University of Oxford3 sites in 1 country62 target enrollmentStarted: January 2016Last updated: February 14, 2024

Conditions

Interventions

Drugs

Trial Snapshot

Phase: Phase 1
Status: Completed
Sponsor: University of Oxford
Enrollment: 62
Locations: 3
Primary Endpoint: To establish the recommended Phase 2 Dose (RP2D) of NUC-3373 that will optimise the risk/benefit reward for the participants, administered weekly (Part 1) and when administered fortnightly (Part 2), as a single I.V. infusion.

Study Overview Study Design Eligibility Criteria Arms & Interventions Outcomes Investigators Sites Records & Identifiers Similar Trials

Study Overview

Brief Summary

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.

Detailed Description

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.

Study Design

Study Type: Interventional
Allocation: Non Randomized
Intervention Model: Parallel
Primary Purpose: Treatment
Masking: None

Eligibility Criteria

Ages: 18 Years to — (Adult, Older Adult)
Sex: All
Accepts Healthy Volunteers: No

Inclusion Criteria

•Provision of signed written informed consent.
•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.
•Age ≥ 18 years.
•Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or
•Life expectancy of ≥ 12 weeks.
•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).
•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.
•Adequate liver function, as determined by: Serum total bilirubin ≤1.5 x ULN, AST and ALT ≤ 2.5 x ULN.
•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 m
•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
•Left Ventricular Ejection Fraction (LVEF) ≥50% on echocardiogram
•Ability to comply with protocol requirements.
•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

Exclusion Criteria

•History of allergic reactions attributed to previous 5-FU or capecitabine treatment.
•History of allergic reactions to any of the components of the diluent solutions supplied with NUC-
•Symptomatic CNS or leptomeningeal metastases.
•Participants with a history of myocardial infarction within the last 5 years or with significant cardiac arrhythmias requiring medication or pacemaker.
•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.
•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.
•Another active cancer excluding basal cell carcinoma or intraepithelial neoplasia (CIN/cervical in situ or melanoma in situ).
•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.
•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.
•Known HIV or known active Hepatitis B or C.
•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.
•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
•Participants who are currently breastfeeding.

Arms & Interventions

Part 1 (weekly administration) NUC-3373 1125mg/m2

Experimental

NUC-3373 1125mg/m2 solution for injection/infusion IV Infusion on Day 1, Day 8, Day 15, Day 22 (28 day cycle).