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Colorectal CancerPhase 2NCT05678257

A Study of NUC-3373 in Combination With Other Agents in Patients With Colorectal Cancer

A Phase 2 study testing Fosifloxuridine Nafalbenamide, Leucovorin and Irinotecan in people with Colorectal Cancer and Colorectal Neoplasms, run by NuCana plc at 59 sites in 6 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
Search all trials

Trial summary

This is a randomized, open-label, dose/schedule optimization study comparing NUC-3373/leucovorin (LV)/irinotecan plus bevacizumab (NUFIRI-bev) to 5-FU/LV/irinotecan plus bevacizumab (FOLFIRI-bev) for the treatment of patients with unresectable metastatic colorectal cancer. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Fosifloxuridine Nafalbenamide, Leucovorin and Irinotecan
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
180 participants
Where
59 sitesin 6 countries
Study dates
18 Apr 2023to 29 Aug 2024
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Provision of written informed consent.
  • Histological or cytological confirmation of colorectal adenocarcinoma (excluding appendiceal and anal canal cancers, as well as signet-ring cell carcinoma) that is unresectable and metastatic.
  • Measurable disease (as defined by RECIST v1.1).
  • Received ≥2 months of a first-line fluoropyrimidine and oxaliplatin-containing regimen for metastatic disease or relapsed within 6 months of completing a fluoropyrimidine and oxaliplatin-containing neoadjuvant/adjuvant therapy. Previous treatment with standard of care chemotherapy regimens in combination with molecular targeted therapies (e.g., VEGF and EGFR pathway inhibitors and immuno-oncology agents) is permitted. Previous treatment with maintenance therapy (e.g., capecitabine) is also allowed. Patients who started on a fluoropyrimidine and oxaliplatin-containing regimen in any setting but must discontinue the oxaliplatin due to.toxicity or allergy (and are now unable to receive oxaliplatin) are considered eligible regardless of the number of cycles of oxaliplatin they received.
  • Known RAS and BRAF status. Patients with wild-type RAS tumours must have received prior treatment with an EGFR inhibitor, unless this was not standard of care according to relevant region-specific treatment recommendations.
  • Known UGT1A1 status, or patient consents to UGT1A1 status testing if unknown.
Show all 17Show fewer
  • Known DPD activity status, or patient consents to DPD status testing if unknown. See exclusion criterion 1.
  • Age ≥18 years.
  • Minimum life expectancy of ≥12 weeks.
  • Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1.
  • Adequate bone marrow function as defined by: absolute neutrophil count (ANC) ≥1.5 × 109/L, platelet count ≥100 × 109/L, and haemoglobin ≥9 g/dL. Patients with benign neutropenia may be discussed on a case-by-case basis with the medical monitor.
  • Adequate liver function, as defined by: serum total bilirubin ≤1.5 × ULN), AST and ALT ≤2.5 × ULN (or ≤5 × ULN if liver metastases are present).
  • Adequate renal function assessed as serum creatinine <1.5 × ULN and glomerular filtration rate ≥50 mL/min (calculated by the Cockcroft-Gault method).
  • Serum albumin ≥3 g/dL.
  • Ability to comply with protocol requirements.
  • Female patients of child-bearing potential must have a negative serum pregnancy test within 7 days prior to the first study drug administration. This criterion does not apply to patients who have had a previous hysterectomy or bilateral oophorectomy. Male patients and female patients of child-bearing potential must agree to practice true abstinence (defined in Section 10.3.1) or to use two forms of contraception, one of which must be highly effective. These forms of contraception must be used from the time of signing consent, throughout the treatment period, and for 6 months following the last dose of any study medication. Oral or injectable contraceptive agents cannot be the sole method of contraception
  • Patients must have been advised to take measures to avoid or minimize exposure of the skin and eyes to UV light, including avoiding sunbathing and solarium use, for the duration of study participation and for a period of 4 weeks following the last dose of study medication

Who cannot join

  • History of hypersensitivity or current contra-indications to 5-FU, FUDR, or capecitabine.
  • History of hypersensitivity or current contra-indication to any of the combination agents required for the study.
  • History of allergic reactions attributed to components of the NUC-3373 drug product formulation.
  • History of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies.
  • History of or known central nervous system or leptomeningeal metastases.
  • Symptomatic ascites, ascites currently requiring drainage procedures or ascites requiring drainage over the prior 3 months.
Show all 31Show fewer
  • Mutant BRAF V600E status.
  • MSI high or dMMR.
  • Prior treatment with irinotecan.
  • Chemotherapy, hormonal therapy, radiotherapy (other than a short cycle of palliative radiotherapy [e.g., for bone pain]*), immunotherapy, biological agents, or exposure to another investigational agent within 21 days (or four times the half-life for molecular targeted agents, whichever is shorter) of first administration of study treatment:
  • Residual toxicities from prior chemotherapy or radiotherapy which have not regressed to Grade ≤1 severity (CTCAE v5.0), except for alopecia and residual Grade 2 neuropathy.
  • History of other malignancies, except adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, surgically excised or potentially curatively treated ductal carcinoma in situ of the breast, or low-grade prostate cancer or patients after prostatectomy. Patients with previous invasive cancers are eligible if treatment was completed >3 years prior to initiating the current study treatment, and the patient has had no evidence or recurrence since then.
  • Presence of an active bacterial or viral infection (including SARS-CoV-2, Herpes Zoster, Varicella Zoster or chickenpox), known Human Immunodeficiency Virus (HIV) positive or known active hepatitis B or C.
  • Presence of any uncontrolled concurrent serious illness, medical condition or other medical history, including laboratory results, which, in the Investigator's opinion, would be likely to interfere with the patient's ability to participate in the study or with the interpretation of the results (refer to protocol for further details).
  • Any condition that, in the judgment of the Investigator, may affect the patient's ability to provide informed consent and undergo study procedures.
  • Patients with a history of haemoptysis (1/2 teaspoon or more of red blood) within 6 months prior to enrolment.
  • Wound healing complications or surgery within 28 days of starting bevacizumab (wound healing must have been fully completed before starting bevacizumab). Investigators may allow patients to initiate treatment with the other study drugs (i.e., NUC-3373/5-FU, LV and irinotecan) on C1D1 but withhold bevacizumab for at least 15 days, but no longer than 28 days, to allow completion of wound healing in patients who would otherwise be eligible for the study, in line with standard local practice and after discussion with the Medical Monitor. Patients who have not received bevacizumab by C2D1 must be replaced.
  • Unhealed wound, active gastric or duodenal ulcer, or bone fracture.
  • Serious thromboembolic event in the 6 months before inclusion.
  • Patients with a history of haemorrhage within 6 months prior to enrolment.
  • Known inherited or acquired bleeding disorders.
  • Red blood cell (RBC) transfusion dependence, defined as requiring more than 2 units of packed RBC transfusions during the 4-week period prior to screening.
  • Uncontrolled hypertension.
  • Severe proteinuria or nephrotic syndrome.
  • Acute intestinal obstruction or sub-obstruction, history of inflammatory intestinal disease or extended resection of the small intestine. Presence of a colic prosthesis.
  • History of abdominal fistulas, trachea-oesophageal fistulas, any other Grade 4 gastrointestinal perforations, non-gastrointestinal fistulas, or intra-abdominal abscesses 6 months prior to screening.
  • Currently pregnant, lactating or breastfeeding.
  • Required concomitant use of brivudine, sorivudine and analogues.
  • Required concomitant use of St John's Wort.
  • Required concomitant use of drugs known to prolong QT/QTc interval.
  • Required 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.

Trial locations and contacts

59 sites in 6 countries.

59 sites in 6 countries

United States16 sites

  • Boston Medical Center

    Boston, Massachusetts, 02118

  • The Christ Hospital Cancer Center

    Cincinnati, Ohio, 45219

  • Texas Oncology - Baylor Charles A. Sammons Cancer Center

    Dallas, Texas, 75246

  • University of Texas Southwestern Medical Center

    Dallas, Texas, 75390

  • Barbara Ann Karmanos Cancer Institute

    Detroit, Michigan, 48201

  • University of Florida Health Medical Oncology - Davis Cancer Pavilion

    Gainesville, Florida, 32610

  • University of Iowa Hospitals and Clinics

    Iowa City, Iowa, 52242

  • Fred Hutchinson Cancer Center at Evergreen Health

    Kirkland, Washington, 98034

  • Norton Cancer Institute

    Louisville, Kentucky, 40202

  • Morristown Medical Center

    Morristown, New Jersey, 07960

  • Helen F. Graham Cancer Center

    Newark, Delaware, 19713

  • USOR - Texas Oncology Northeast Texas

    Tyler, Texas, 75702

  • Northwest Cancer Specialists, P.C. dba Compass Oncology - Vancouver Cancer Center

    Vancouver, Washington, 98684

  • Georgetown University Medical Center

    Washington D.C., District of Columbia, 20007

  • Cancer Center of Kansas

    Wichita, Kansas, 67214

  • University of Massachusetts Worcester

    Worcester, Massachusetts, 01655

Other trials in United States

Spain14 sites

  • Hospital Universitario Fundación Alcorcón

    Alcorcón, Madrid, 28922

  • Institut Català d'Oncologia - ICO Badalona - Hospital Universitari Germans Trias i Pujol

    Badalona, Barcelona, 08916

  • Hospital de la Santa Creu i Sant Pau

    Barcelona, 08041

  • Hospital Universitari Vall d'Hebrón

    Barcelona, 8035

  • Hospital Duran i Reynals

    Barcelona, 8908

  • Hospital de León

    León, 24008

  • Hospital Universitari Arnau de Vilanova

    Lleida, 25198

  • Hospital General Universitario Gregorio Marañón

    Madrid, 28007

  • MD Anderson Cancer Center Madrid

    Madrid, 28033

  • Hospital Universitario 12 de Octubre

    Madrid, 28041

  • Hospital Universitario Puerta de Hierro

    Majadahonda, Madrid, 28222

  • Hospital Universitario Virgen de la Victoria

    Málaga, 29010

  • Complejo Hospitalario Universitario de Santiago (CHUS)

    Santiago de Compostela, La Coruña, 15706

  • Hospital Universitario Virgen del Rocío

    Seville, 41013

Other trials in Spain

France9 sites

  • Centre Hospitalier Régional et Universitaire de Besançon - Hôpital Jean-Minjoz

    Besançon, Doubs, 25000

  • Institut Bergonié

    Bordeaux, Gironde, 33076

  • Centre Georges-François Leclerc

    Dijon, Bourgogne-Franche-Comté, 21079

  • Hôpital Européen Marseille

    Marseille, Bouches-du-Rhône, 13003

  • Centre Hospitalier UniversitaireNantes - Hôtel Dieu

    Nantes, 44000

  • Hôpital Européen Georges-Pompidou

    Paris, Île-de-France Region, 75015

  • Centre Hospitalier Universitaire de Poitiers

    Poitiers, Vienne, 86000

  • Strasbourg Oncology Liberale - Clinique Sainte-Anne

    Strasbourg, Alsace, 67000

  • Hôpital Foch

    Suresnes, Île-de-France Region, 92150

Other trials in France

Italy8 sites

  • Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona

    Ancona, 60126

  • Ospedale Santa Maria delle Croci di Ravenna

    Faenza, Ravenna, 48121

  • Azienda Ospedaliero Universitaria Careggi

    Florence, Tuscany, 50134

  • Fondazione IRCCS Istituto Nazionale dei Tumori

    Milan, Lombardy, 20133

  • Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda

    Milan, 20162

  • Azienda Ospedaliera Universitaria - Università degli Studi della Campania Luigi Vanvitelli

    Naples, Campania, 80131

  • Istituto Oncologico Veneto - IRCCS

    Padova, Veneto, 35128

  • Azienda Ospedaliera Regionale San Carlo

    Potenza, 85100

Other trials in Italy

United Kingdom8 sites

  • Velindre University NHS Trust

    Cardiff, CF14 2TL

  • NHS Greater Glasgow and Clyde

    Glasgow, G51 4TF

  • University College London Hospitals NHS Foundation Trust

    London, Greater London, NW1 2PG

  • Royal Free London NHS Foundation Trust

    London, Greater London, NW3 2QG

  • Guy's and Saint Thomas' NHS Foundation Trust

    London, Greater London, SE1 9RT

  • The Christie NHS Foundation Trust

    Manchester, Lancashire, M20 4BX

  • Mount Vernon Cancer Centre - East and North Hertfordshire NHS Trust

    Northwood, Middlesex, HA6 2RN

  • Queen's Hospital

    Romford, Essex, RM7 OAG

Other trials in United Kingdom

Germany4 sites

  • Charité Campus Virchow-Klinikum

    Berlin, 13353

  • Krankenhaus Nordwest

    Frankfurt am Main, Hesse, 60488

  • München Klinik Neuperlach

    München, Bavaria, 81737

  • Universitätsklinik Ulm - Oberen Eselsberg

    Ulm, Tübingen, 89081

Other trials in Germany

About this study

Official title: A Randomised, Open-label, Phase II, Dose/Schedule Optimisation Study of NUC-3373/Leucovorin/Irinotecan Plus Bevacizumab (NUFIRI-bev) Versus 5-FU/Leucovorin/Irinotecan Plus Bevacizumab (FOLFIRI-bev) for the Treatment of Patients With Previously Treated Unresectable Metastatic Colorectal Cancer

This is a randomized, open-label, dose/schedule optimization study comparing NUC-3373/leucovorin (LV)/irinotecan plus bevacizumab (NUFIRI-bev) to 5-FU/LV/irinotecan plus bevacizumab (FOLFIRI-bev) for the treatment of patients with unresectable metastatic colorectal cancer.

A total of 171 patients will be randomized 1:1:1 to either NUFIRI-bev on a weekly NUC-3373 schedule, NUFIRI-bev based on an alternate weekly NUC-3373 schedule, or FOLFIRI bev on an alternate weekly schedule. The main objectives are to assess and compare the efficacy and safety of the 3 regimens. Pharmacokinetics will be assessed on the 2 NUFIRI arms.

Being tested
Fosifloxuridine Nafalbenamide, Leucovorin, Irinotecan, Bevacizumab, 5-FU
Keywords
Relapsed metastatic adenocarcinoma of colon/rectum, NUC-3373, Fosifloxuridine nafalbenamide, Leucovorin, Irinotecan, Bevacizumab, Antineoplastic agents, Chemotherapy, Second-line chemotherapy, Locally advanced cancer, Metastatic cancer, Neoplasm, 5-FU
Medical subject headings
Colorectal Neoplasms, Colonic Neoplasms, Neoplasm Metastasis, Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Fosifloxuridine NafalbenamideDrug

    Also called NUC-3373, Nucleotide analogue

    Intravenous infusion

  • LeucovorinDrug

    Also called Folinic acid, LV

    Intravenous infusion

  • IrinotecanDrug

    Also called Campto, Camptosar

    Intravenous infusion

  • BevacizumabBiological

    Also called Avastin, Zirabev

    Intravenous infusion

  • 5-FUDrug

    Also called 5FU, 5-fluorouracil, Fluorouracil

    Intravenous infusion

Study groups in NCT05678257
Study groupRoleWhat they receive
NUFIRI-bev on a Q1W NUC-3373 scheduleExperimentalArm A: Study treatment will be administered in 28-day cycles as follows: 1. Bevacizumab 5 mg/kg on Days 1 and 15: * 90 minutes for the first dose * 60 minutes for the second dose (if first dose is tolerated) * 30 minutes for subsequent doses (if second dose is tolerated) 2. LV 400 mg/m2 (or equivalent levo-LV) over 120 minutes on Days 1, 8, 15, and 22. 3. Irinotecan 180 mg/m2 over 90 minutes (concurrently with the LV infusion) on Days 1 and 15. 4. NUC-3373 1500 mg/m2 over 120 minutes on Days 1, 8, 15, and 22.
Receives: Drug: Fosifloxuridine Nafalbenamide; Drug: Leucovorin; Drug: Irinotecan; Biological: Bevacizumab
NUFIRI-bev on a Q2W NUC-3373 scheduleExperimentalArm B: Study treatment will be administered in 28-day cycles as follows: 1. Bevacizumab 5 mg/kg on Days 1 and 15: * 90 minutes for the first dose * 60 minutes for the second dose (if first dose is tolerated) * 30 minutes for subsequent doses (if second dose is tolerated) 2. LV 400 mg/m2 (or equivalent levo-LV) over 120 minutes on Days 1 and 15. 3. Irinotecan 180 mg/m2 over 90 minutes (concurrently with the LV infusion) on Days 1 and 15. 4. NUC-3373 1500 mg/m2 over 120 minutes on Days 1 and 15.
Receives: Drug: Fosifloxuridine Nafalbenamide; Drug: Leucovorin; Drug: Irinotecan; Biological: Bevacizumab
FOLFIRI-bev on a Q2W scheduleActive comparatorArm C: Study treatment will be administered in 28-day cycles as follows: 1. Bevacizumab 5 mg/kg on Days 1 and 15: * 90 minutes for the first dose * 60 minutes for the second dose (if first dose is tolerated) * 30 minutes for subsequent doses (if second dose is tolerated) 2. LV 400 mg/m2 (or equivalent levo-LV) over 120 minutes on Days 1 and 15. 3. Irinotecan 180 mg/m2 over 90 minutes (concurrently with the LV infusion) on Days 1 and 15. 4. 5-FU 400 mg/m2 bolus on Days 1 and 15. 5. 5-FU 2400 mg/m2 infusion over 46 hours on Days 1 and 15.
Receives: Drug: Leucovorin; Drug: Irinotecan; Biological: Bevacizumab; Drug: 5-FU

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Median Progress-free Survival (PFS)

    PFS assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, defined as the time from randomisation to the first observation of objective tumour progression or death from any cause. Progression was defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in non-target lesions, or the appearance of new lesions.

    Measured: Assessed from baseline to 30 days after last dose of study drug, up to 16 months

Secondary outcomes (2)

  1. Number of Patients Achieving a Reduction in Tumour Volume

    Objective response rate, defined as the percentage of patients achieving a complete (CR) or partial response (PR) to treatment. Response was measured by MRI scan and assessed per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) criteria:

    CR= disappearance of all target lesions PR= at least a 30% decrease in the sum of the longest diameter of target lesions

    Measured: Assessed from baseline to 30 days after last dose of study drug, up to 16 months

  2. Number of Patients Achieving Disease Control

    Disease control rate, defined as the number of patients achieving a response (CR or PR) or stable disease (SD) as their best overall response. Disease control was measured by MRI scan and assessed using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) criteria:

    CR= disappearance of all target lesions PR= at least a 30% decrease in the sum of the longest diameter of target lesions SD= neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease

    Measured: Assessed from baseline to 30 days after last dose of study drug, up to 16 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Jan 2023
  2. Study start18 Apr 2023
  3. Primary completion29 Aug 2024
  4. Study completion29 Aug 2024

Why it stopped: A pre-planned initial analysis concluded that the study was unlikely to achieve its primary objective of demonstrating superior progression-free survival. Based on the Steering Committee's recommendation, the Sponsor has closed the study.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
180 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05678257
Sponsor's protocol ID
NuTide:323
Other IDs
2022-001459-17
Status last verified
Aug 2025
First submitted
22 Dec 2022
Last updated
12 Sep 2025
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Fosifloxuridine Nafalbenamide, Leucovorin and Irinotecan in people with Colorectal Cancer and Colorectal Neoplasms, run by NuCana plc at 59 sites in 6 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 12 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 59 sites in United States, Spain, France, Italy, United Kingdom and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 12 Sep 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Median Progress-free Survival (PFS) (time frame: Assessed from baseline to 30 days after last dose of study drug, up to 16 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05678257.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Sep 2025.

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