NUC-3373 in Advanced Solid Tumours

NCT02723240 | Completed Phase 1 DMC

• 2 other identifiers: OCTO_0742015-002250-13
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 3

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.

Conditions

Cancer

Keywords

NUC-3373; Dose escalation; Nucleotide Analogue

Outcome Measures

Primary Outcomes (1)

• 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.

  The RP2D is the most appropriate dose that will optimise the risk/benefit reward for the participants. RP2D determination will take into consideration the plasma PK, PD assessments, the nature of the PK/PD relationship, any efficacy signals or any adverse events observed during the conduct of the dose-escalation and the available non clinical data. The RP2D will be determined by dose escalation with sequential participants receiving increasing doses of NUC-3373 in a standard '3 + 3' cohort design. Dose escalation will stop when the Maximum Tolerated Dose (MTD)/RP2D have been defined for that Part or a decision is made by the Trial Management Group to halt enrolment.

  To decide if the next cohort can be opened at a higher dose level, the Trial Management Group (TMG) will review available data (e.g. safety profile) once all participants in the preceding cohort have completed the first cycle through to Day 28.

Secondary Outcomes (12)

• Dose Limiting Toxicities (DLT) to assess the tolerability of NUC-3373

  Assessment starts at first IMP administration (Cycle 1 Day 1) until the first cycle completion (Day 28)

• Dose Limiting Toxicities (DLT) and SAEs/AEs to assess the safety of NUC-3373

  Adverse event monitoring starts at IMP administration (Day 1) until 28 days after the final dose of IMP has been administered.

• Analysis of NUC-3373 metabolites in plasma to determine Area under the curve (AUC)

  PK samples will be collected on Cycle 1 Day 1 and Cycle 1 Day 15

• Analysis of NUC-3373 metabolites in plasma to determine Peak Plasma Concentration (Cmax)

  PK samples will be collected on Cycle 1 Day 1 and Cycle 1 Day 15

• Analysis of NUC-3373 metabolites in plasma to determine Clearance

  PK samples will be collected on Cycle 1 Day 1 and Cycle 1 Day 15

Other Outcomes (2)

• Tertiary/Exploratory Objectives: Translational study to establish the expression of certain biomarkers in PBMCs and biopsy samples which may help to predict patients more likely to benefit from NUC-3373 over 5-FU.

  through study completion, an average of 1 per year

• Tertiary/Exploratory Outcomes. To collect and bank samples for use in future ethically approved studies to explore potential stratification based on mutations e.g. KRas, VEGF and BRAF. RNA will be analysed using a RNA scope.

  Screening/Baseline

Study Arms (12)

Part 1 (weekly administration) NUC-3373 125mg/m2

EXPERIMENTAL

NUC-3373 125mg/m2 solution for injection/infusion IV Infusion on Day 1, Day 8, Day 15, Day 22 (28 day cycle). Participants can remain on study and receive treatment until disease progression or unacceptable toxicity occurs.

Drug: NUC-3373

Part 1 (weekly administration) NUC-3373 250mg/m2

EXPERIMENTAL

NUC-3373 250mg/m2 solution for injection/infusion IV Infusion on Day 1, Day 8, Day 15, Day 22 (28 day cycle). Participants can remain on study and receive treatment until disease progression or unacceptable toxicity occurs.

Drug: NUC-3373

Part 1 (weekly administration) NUC-3373 500mg/m2

EXPERIMENTAL

NUC-3373 500mg/m2 solution for injection/infusion IV Infusion on Day 1, Day 8, Day 15, Day 22 (28 day cycle). Participants can remain on study and receive treatment until disease progression or unacceptable toxicity occurs.

Drug: NUC-3373

Part 1 (weekly administration) NUC-3373 750mg/m2

EXPERIMENTAL

NUC-3373 750mg/m2 solution for injection/infusion IV Infusion on Day 1, Day 8, Day 15, Day 22 (28 day cycle). Participants can remain on study and receive treatment until disease progression or unacceptable toxicity occurs.

Drug: NUC-3373

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). Participants can remain on study and receive treatment until disease progression or unacceptable toxicity occurs.

Drug: NUC-3373

Part 1 (weekly administration) NUC-3373 1500mg/m2

EXPERIMENTAL

NUC-3373 1500mg/m2 solution for injection/infusion IV Infusion on Day 1, Day 8, Day 15, Day 22 (28 day cycle). Participants can remain on study and receive treatment until disease progression or unacceptable toxicity occurs.

Drug: NUC-3373

Part 1 (weekly administration) NUC-3373 1875mg/m2

EXPERIMENTAL

NUC-3373 1875mg/m2 solution for injection/infusion IV Infusion on Day 1, Day 8, Day 15, Day 22 (28 day cycle). Participants can remain on study and receive treatment until disease progression or unacceptable toxicity occurs.

Drug: NUC-3373

Part 1 (weekly administration) NUC-3373 2500mg/m2

EXPERIMENTAL

NUC-3373 2500mg/m2 solution for injection/infusion IV Infusion on Day 1, Day 8, Day 15, Day 22 (28 day cycle). Participants can remain on study and receive treatment until disease progression or unacceptable toxicity occurs.

Drug: NUC-3373

Part 1 (weekly administration) NUC-3373 3250mg/m2

EXPERIMENTAL

NUC-3373 3250mg/m2 solution for injection/infusion IV Infusion on Day 1, Day 8, Day 15, Day 22 (28 day cycle). Participants can remain on study and receive treatment until disease progression or unacceptable toxicity occurs.

Drug: NUC-3373

Part 2 (two weekly administration) NUC-3373 1500mg/m2

EXPERIMENTAL

NUC-3373 1500mg/m2 solution for injection/infusion IV Infusion on Day 1, Day 15 (28 day cycle). Participants can remain on study and receive treatment until disease progression or unacceptable toxicity occurs.

Drug: NUC-3373

Part 2 (two weekly administration) NUC-3373 1875mg/m2

EXPERIMENTAL

NUC-3373 1875mg/m2 solution for injection/infusion IV Infusion on Day 1, Day 15 (28 day cycle). Participants can remain on study and receive treatment until disease progression or unacceptable toxicity occurs.

Drug: NUC-3373

Part 2 (two weekly administration) NUC-3373 2500mg/m2

EXPERIMENTAL

NUC-3373 2500mg/m2 solution for injection/infusion IV Infusion on Day 1, Day 15 (28 day cycle). Participants can remain on study and receive treatment until disease progression or unacceptable toxicity occurs.

Drug: NUC-3373

Interventions

NUC-3373 DRUG

Part 1 (weekly administration) NUC-3373 1125mg/m2; Part 1 (weekly administration) NUC-3373 125mg/m2; Part 1 (weekly administration) NUC-3373 1500mg/m2; Part 1 (weekly administration) NUC-3373 1875mg/m2; Part 1 (weekly administration) NUC-3373 2500mg/m2; Part 1 (weekly administration) NUC-3373 250mg/m2; Part 1 (weekly administration) NUC-3373 3250mg/m2; Part 1 (weekly administration) NUC-3373 500mg/m2; Part 1 (weekly administration) NUC-3373 750mg/m2; Part 2 (two weekly administration) NUC-3373 1500mg/m2; Part 2 (two weekly administration) NUC-3373 1875mg/m2; Part 2 (two weekly administration) NUC-3373 2500mg/m2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 2.
• 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 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
• 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 1. .

You may not qualify if:

• 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-3373.
• 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.
• 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.

Sponsors & Collaborators

• University of Oxford: lead

Study Sites (3)

Belfast City Hospital

Belfast, BT9 7AB, United Kingdom

Location

Beatson, West of Scotland Cancer Centre

Glasgow, G12 OYN, United Kingdom

Location

Oxford University Hospitals NHS Trust

Oxford, OX3 7LE, United Kingdom

Location

Related Publications (1)

• Spiliopoulou P, Kazmi F, Aroldi F, Holmes T, Thompson D, Griffiths L, Qi C, Parkes M, Lord S, Veal GJ, Harrison DJ, Coyle VM, Graham J, Jeffry Evans TR, Blagden SP. A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301). J Exp Clin Cancer Res. 2024 Apr 2;43(1):100. doi: 10.1186/s13046-024-03010-1.

  PMID: 38566164 DERIVED

MeSH Terms

Conditions

Neoplasms

Study Officials

• Sarah P Blagden, PhD, FRCP

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 8, 2015
• First Posted: March 30, 2016
• Study Start: January 1, 2016
• Primary Completion: February 24, 2020
• Study Completion: February 24, 2021
• Last Updated: February 14, 2024

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (3)