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

NCT05678257 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: NuTide:3232022-001459-17
• Study Type: interventional
• Target: 180
• Locations: 6 countries
• Sites: 59

Brief 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. 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.

Conditions

Colorectal Cancer; Colorectal Neoplasms; Colorectal Adenocarcinoma; Colorectal Cancer Metastatic; Neoplasm, Colorectal

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

Outcome Measures

Primary Outcomes (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.

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

Secondary Outcomes (2)

• Number of Patients Achieving a Reduction in Tumour Volume

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

• Number of Patients Achieving Disease Control

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

Study Arms (3)

NUFIRI-bev on a Q1W NUC-3373 schedule

EXPERIMENTAL

Arm 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.

Drug: Fosifloxuridine Nafalbenamide; Drug: Leucovorin; Drug: Irinotecan; Biological: Bevacizumab

NUFIRI-bev on a Q2W NUC-3373 schedule

EXPERIMENTAL

Arm 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.

Drug: Fosifloxuridine Nafalbenamide; Drug: Leucovorin; Drug: Irinotecan; Biological: Bevacizumab

FOLFIRI-bev on a Q2W schedule

ACTIVE COMPARATOR

Arm 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.

Drug: Leucovorin; Drug: Irinotecan; Biological: Bevacizumab; Drug: 5-FU

Interventions

Fosifloxuridine Nafalbenamide DRUG

Intravenous infusion

Also known as: NUC-3373, Nucleotide analogue

NUFIRI-bev on a Q1W NUC-3373 schedule; NUFIRI-bev on a Q2W NUC-3373 schedule

Leucovorin DRUG

Intravenous infusion

Also known as: Folinic acid, LV

FOLFIRI-bev on a Q2W schedule; NUFIRI-bev on a Q1W NUC-3373 schedule; NUFIRI-bev on a Q2W NUC-3373 schedule

Irinotecan DRUG

Intravenous infusion

Also known as: Campto, Camptosar

FOLFIRI-bev on a Q2W schedule; NUFIRI-bev on a Q1W NUC-3373 schedule; NUFIRI-bev on a Q2W NUC-3373 schedule

Bevacizumab BIOLOGICAL

Intravenous infusion

Also known as: Avastin, Zirabev

FOLFIRI-bev on a Q2W schedule; NUFIRI-bev on a Q1W NUC-3373 schedule; NUFIRI-bev on a Q2W NUC-3373 schedule

5-FU DRUG

Intravenous infusion

Also known as: 5FU, 5-fluorouracil, Fluorouracil

FOLFIRI-bev on a Q2W schedule

Eligibility Criteria

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

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• NuCana plc: lead

Study Sites (59)

Helen F. Graham Cancer Center

Newark, Delaware, 19713, United States

Location

Georgetown University Medical Center

Washington D.C., District of Columbia, 20007, United States

Location

University of Florida Health Medical Oncology - Davis Cancer Pavilion

Gainesville, Florida, 32610, United States

Location

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

Cancer Center of Kansas

Wichita, Kansas, 67214, United States

Location

Norton Cancer Institute

Louisville, Kentucky, 40202, United States

Location

Boston Medical Center

Boston, Massachusetts, 02118, United States

Location

University of Massachusetts Worcester

Worcester, Massachusetts, 01655, United States

Location

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Morristown Medical Center

Morristown, New Jersey, 07960, United States

Location

The Christ Hospital Cancer Center

Cincinnati, Ohio, 45219, United States

Location

Texas Oncology - Baylor Charles A. Sammons Cancer Center

Dallas, Texas, 75246, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

USOR - Texas Oncology Northeast Texas

Tyler, Texas, 75702, United States

Location

Fred Hutchinson Cancer Center at Evergreen Health

Kirkland, Washington, 98034, United States

Location

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

Vancouver, Washington, 98684, United States

Location

Strasbourg Oncology Liberale - Clinique Sainte-Anne

Strasbourg, Alsace, 67000, France

Location

Hôpital Européen Marseille

Marseille, Bouches-du-Rhône, 13003, France

Location

Centre Georges-François Leclerc

Dijon, Bourgogne-Franche-Comté, 21079, France

Location

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

Besançon, Doubs, 25000, France

Location

Institut Bergonié

Bordeaux, Gironde, 33076, France

Location

Centre Hospitalier Universitaire de Poitiers

Poitiers, Vienne, 86000, France

Location

Centre Hospitalier UniversitaireNantes - Hôtel Dieu

Nantes, 44000, France

Location

Hôpital Européen Georges-Pompidou

Paris, Île-de-France Region, 75015, France

Location

Hôpital Foch

Suresnes, Île-de-France Region, 92150, France

Location

München Klinik Neuperlach

München, Bavaria, 81737, Germany

Location

Krankenhaus Nordwest

Frankfurt am Main, Hesse, 60488, Germany

Location

Universitätsklinik Ulm - Oberen Eselsberg

Ulm, Tübingen, 89081, Germany

Location

Charité Campus Virchow-Klinikum

Berlin, 13353, Germany

Location

Azienda Ospedaliera Universitaria - Università degli Studi della Campania Luigi Vanvitelli

Napoli, Campania, 80131, Italy

Location

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Lombardy, 20133, Italy

Location

Ospedale Santa Maria delle Croci di Ravenna

Faenza, Ravenna, 48121, Italy

Location

Azienda Ospedaliero Universitaria Careggi

Florence, Tuscany, 50134, Italy

Location

Istituto Oncologico Veneto - IRCCS

Padua, Veneto, 35128, Italy

Location

Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona

Ancona, 60126, Italy

Location

Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda

Milan, 20162, Italy

Location

Azienda Ospedaliera Regionale San Carlo

Potenza, 85100, Italy

Location

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

Badalona, Barcelona, 08916, Spain

Location

Complejo Hospitalario Universitario de Santiago (CHUS)

Santiago de Compostela, La Coruña, 15706, Spain

Location

Hospital Universitario Fundación Alcorcón

Alcorcón, Madrid, 28922, Spain

Location

Hospital Universitario Puerta de Hierro

Majadahonda, Madrid, 28222, Spain

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, 08041, Spain

Location

Hospital Universitari Vall d'Hebrón

Barcelona, 8035, Spain

Location

Hospital Duran i Reynals

Barcelona, 8908, Spain

Location

Hospital de León

León, 24008, Spain

Location

Hospital Universitari Arnau de Vilanova

Lleida, 25198, Spain

Location

Hospital General Universitario Gregorio Marañón

Madrid, 28007, Spain

Location

MD Anderson Cancer Center Madrid

Madrid, 28033, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Hospital Universitario Virgen de la Victoria

Málaga, 29010, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, 41013, Spain

Location

Queen's Hospital

Romford, Essex, RM7 OAG, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, Greater London, NW1 2PG, United Kingdom

Location

Royal Free London NHS Foundation Trust

London, Greater London, NW3 2QG, United Kingdom

Location

Guy's and Saint Thomas' NHS Foundation Trust

London, Greater London, SE1 9RT, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, Lancashire, M20 4BX, United Kingdom

Location

Mount Vernon Cancer Centre - East and North Hertfordshire NHS Trust

Northwood, Middlesex, HA6 2RN, United Kingdom

Location

Velindre University NHS Trust

Cardiff, CF14 2TL, United Kingdom

Location

NHS Greater Glasgow and Clyde

Glasgow, G51 4TF, United Kingdom

Location

MeSH Terms

Conditions

Colorectal Neoplasms; Colonic Neoplasms; Neoplasm Metastasis; Neoplasms

Interventions

Leucovorin; Irinotecan; Bevacizumab; Fluorouracil

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes; Camptothecin; Alkaloids; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring

Limitations and Caveats

Due to the early closure of the study, many patients were censored for the efficacy endpoints and the data should therefore be interpreted with caution.

Results Point of Contact

• Title: Medical and Scientific Affairs Department
• Organization: NuCana plc

info@nucana.com

+44 131 357 1111

Study Officials

• Elisabeth Oelmann, MD, PhD

  NuCana plc

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 22, 2022
• First Posted: January 10, 2023
• Study Start: April 18, 2023
• Primary Completion: August 29, 2024
• Study Completion: August 29, 2024
• Last Updated: September 12, 2025
• Results First Posted: September 12, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (16); IT (8); FR (9); ES (14); GB (8); DE (4)