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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Colorectal Neoplasms; Colorectal Cancer; Colorectal Cancer Metastatic; Colorectal Adenocarcinoma; Neoplasm, Colorectal
• Intervention / Treatment: Drug: Fosifloxuridine Nafalbenamide; Drug: Leucovorin; Drug: Irinotecan; Biological: Bevacizumab; Drug: 5-FU

• Study Type: Interventional
• Enrollment (Actual): 182
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: NuTide:323 Project Manager; Phone Number: +44 (0)357 1111; Email: NuTide323@nucana.com

Study Locations

• France
  • Nantes, France, 44000
    • Centre Hospitalier UniversitaireNantes - Hôtel Dieu
  • Alsace
    • Strasbourg, Alsace, France, 67000
      • Strasbourg Oncology Liberale - Clinique Sainte-Anne
  • Bouches-du-Rhône
    • Marseille, Bouches-du-Rhône, France, 13003
      • Hôpital Européen Marseille
  • Bourgogne-Franche-Comté
    • Dijon, Bourgogne-Franche-Comté, France, 21079
      • Centre Georges-François Leclerc
  • Doubs
    • Besançon, Doubs, France, 25000
      • Centre Hospitalier Regional et Universitaire de Besancon - Hopital Jean-Minjoz
  • Gironde
    • Bordeaux, Gironde, France, 33076
      • Institut Bergonie
  • Vienne
    • Poitiers, Vienne, France, 86000
      • Centre Hospitalier Universitaire de Poitiers
  • Île-de-France
    • Paris, Île-de-France, France, 75015
      • Hopital Europeen Georges-Pompidou
    • Suresnes, Île-de-France, France, 92150
      • Hopital Foch
• Germany
  • Berlin, Germany, 13353
    • Charité Campus Virchow-Klinikum
  • Bavaria
    • München, Bavaria, Germany, 81737
      • München Klinik Neuperlach
  • Hesse
    • Frankfurt, Hesse, Germany, 60488
      • Krankenhaus Nordwest
  • Tübingen
    • Ulm, Tübingen, Germany, 89081
      • Universitätsklinik Ulm - Oberen Eselsberg
• Italy
  • Ancona, Italy, 60126
    • Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona
  • Milano, Italy, 20162
    • Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda
  • Potenza, Italy, 85100
    • Azienda Ospedaliera Regionale San Carlo
  • Campania
    • Napoli, Campania, Italy, 80131
      • Azienda Ospedaliera Universitaria - Università degli Studi della Campania Luigi Vanvitelli
  • Lombardia
    • Milano, Lombardia, Italy, 20133
      • Fondazione IRCCS Istituto Nazionale dei Tumori
  • Ravenna
    • Faenza, Ravenna, Italy, 48121
      • Ospedale Santa Maria delle Croci di Ravenna
  • Toscana
    • Firenze, Toscana, Italy, 50134
      • Azienda Ospedaliero Universitaria Careggi
  • Veneto
    • Padova, Veneto, Italy, 35128
      • Istituto Oncologico Veneto - IRCCS
• Spain
  • Barcelona, Spain, 8035
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain, 8908
    • Hospital Duran I Reynals
  • León, Spain, 24008
    • Hospital de Leon
  • Lleida, Spain, 25198
    • Hospital Universitari Arnau de Vilanova
  • Madrid, Spain, 28041
    • Hospital Universitario 12 De Octubre
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon
  • Madrid, Spain, 28033
    • MD Anderson Cancer Center Madrid
  • Málaga, Spain, 29010
    • Hospital Universitario Virgen de la Victoria
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocío
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Institut Català d'Oncologia - ICO Badalona - Hospital Universitari Germans Trias i Pujol
  • La Coruña
    • Santiago de Compostela, La Coruña, Spain, 15706
      • Complejo Hospitalario Universitario de Santiago (CHUS)
  • Madrid
    • Alcorcón, Madrid, Spain, 28922
      • Hospital Universitario Fundacion Alcorcon
    • Majadahonda, Madrid, Spain, 28222
      • Hospital Universitario Puerta de Hierro
• United Kingdom
  • Cardiff, United Kingdom, CF14 2TL
    • Velindre University NHS Trust
  • Glasgow, United Kingdom, G51 4TF
    • NHS Greater Glasgow and Clyde
  • Essex
    • Romford, Essex, United Kingdom, RM7 OAG
      • Queen's Hospital
  • Greater London
    • London, Greater London, United Kingdom, NW3 2QG
      • Royal Free London NHS Foundation Trust
    • London, Greater London, United Kingdom, NW1 2PG
      • University College London Hospitals NHS Foundation Trust
    • London, Greater London, United Kingdom, SE1 9RT
      • Guy's and Saint Thomas' NHS Foundation Trust
  • Lancashire
    • Manchester, Lancashire, United Kingdom, M20 4BX
      • The Christie NHS Foundation Trust
  • Middlesex
    • Northwood, Middlesex, United Kingdom, HA6 2RN
      • Mount Vernon Cancer Centre - East and North Hertfordshire NHS Trust
• United States
  • Delaware
    • Newark, Delaware, United States, 19713
      • Helen F. Graham Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Health Medical Oncology - Davis Cancer Pavilion
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kansas
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Norton Cancer Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Worcester
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Morristown Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • The Christ Hospital Cancer Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Dallas, Texas, United States, 75246
      • Texas Oncology - Baylor Charles A. Sammons Cancer Center
    • Tyler, Texas, United States, 75702
      • USOR - Texas Oncology Northeast Texas
  • Washington
    • Kirkland, Washington, United States, 98034
      • Fred Hutchinson Cancer Center at Evergreen Health
    • Vancouver, Washington, United States, 98684
      • Northwest Cancer Specialists, P.C. dba Compass Oncology - Vancouver Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Provision of written informed consent.
2. 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.
3. Measurable disease (as defined by RECIST v1.1).
4. 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.
5. 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.
6. Known UGT1A1 status, or patient consents to UGT1A1 status testing if unknown.
7. Known DPD activity status, or patient consents to DPD status testing if unknown. See exclusion criterion 1.
8. Age ≥18 years.
9. Minimum life expectancy of ≥12 weeks.
10. Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1.
11. 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.
12. 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).
13. Adequate renal function assessed as serum creatinine <1.5 × ULN and glomerular filtration rate ≥50 mL/min (calculated by the Cockcroft-Gault method).
14. Serum albumin ≥3 g/dL.
15. Ability to comply with protocol requirements.
16. 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
17. 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

Exclusion Criteria:

1. History of hypersensitivity or current contra-indications to 5-FU, FUDR, or capecitabine.
2. History of hypersensitivity or current contra-indication to any of the combination agents required for the study.
3. History of allergic reactions attributed to components of the NUC-3373 drug product formulation.
4. History of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies.
5. History of or known central nervous system or leptomeningeal metastases.
6. Symptomatic ascites, ascites currently requiring drainage procedures or ascites requiring drainage over the prior 3 months.
7. Mutant BRAF V600E status.
8. MSI high or dMMR.
9. Prior treatment with irinotecan.
10. 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:
11. 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.
12. 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.
13. 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.
14. 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).
15. Any condition that, in the judgment of the Investigator, may affect the patient's ability to provide informed consent and undergo study procedures.
16. Patients with a history of haemoptysis (1/2 teaspoon or more of red blood) within 6 months prior to enrolment.
17. 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.
18. Unhealed wound, active gastric or duodenal ulcer, or bone fracture.
19. Serious thromboembolic event in the 6 months before inclusion.
20. Patients with a history of haemorrhage within 6 months prior to enrolment.
21. Known inherited or acquired bleeding disorders.
22. 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.
23. Uncontrolled hypertension.
24. Severe proteinuria or nephrotic syndrome.
25. Acute intestinal obstruction or sub-obstruction, history of inflammatory intestinal disease or extended resection of the small intestine. Presence of a colic prosthesis.
26. 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.
27. Currently pregnant, lactating or breastfeeding.
28. Required concomitant use of brivudine, sorivudine and analogues.
29. Required concomitant use of St John's Wort.
30. Required concomitant use of drugs known to prolong QT/QTc interval.
31. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NUFIRI-bev on a Q1W NUC-3373 schedule; Arm A: Study treatment will be administered in 28-day cycles as follows: Bevacizumab 5 mg/kg on Days 1 and 15:90 minutes for the first dose60 minutes for the second dose (if first dose is tolerated)30 minutes for subsequent doses (if second dose is tolerated); LV 400 mg/m2 (or equivalent levo-LV) over 120 minutes on Days 1, 8, 15, and 22.; Irinotecan 180 mg/m2 over 90 minutes (concurrently with the LV infusion) on Days 1 and 15.; NUC-3373 1500 mg/m2 over 120 minutes on Days 1, 8, 15, and 22.	Drug: Fosifloxuridine Nafalbenamide; Intravenous infusion; Other Names: Nucleotide analogue; NUC-3373; Drug: Leucovorin; Intravenous infusion; Other Names: LV; Folinic acid; Drug: Irinotecan; Intravenous infusion; Other Names: Campto; Camptosar; Biological: Bevacizumab; Intravenous infusion; Other Names: Avastin; Zirabev
Experimental: NUFIRI-bev on a Q2W NUC-3373 schedule; Arm B: Study treatment will be administered in 28-day cycles as follows: Bevacizumab 5 mg/kg on Days 1 and 15:90 minutes for the first dose60 minutes for the second dose (if first dose is tolerated)30 minutes for subsequent doses (if second dose is tolerated); LV 400 mg/m2 (or equivalent levo-LV) over 120 minutes on Days 1 and 15.; Irinotecan 180 mg/m2 over 90 minutes (concurrently with the LV infusion) on Days 1 and 15.; NUC-3373 1500 mg/m2 over 120 minutes on Days 1 and 15.	Drug: Fosifloxuridine Nafalbenamide; Intravenous infusion; Other Names: Nucleotide analogue; NUC-3373; Drug: Leucovorin; Intravenous infusion; Other Names: LV; Folinic acid; Drug: Irinotecan; Intravenous infusion; Other Names: Campto; Camptosar; Biological: Bevacizumab; Intravenous infusion; Other Names: Avastin; Zirabev
Active Comparator: FOLFIRI-bev on a Q2W schedule; Arm C: Study treatment will be administered in 28-day cycles as follows: Bevacizumab 5 mg/kg on Days 1 and 15:90 minutes for the first dose60 minutes for the second dose (if first dose is tolerated)30 minutes for subsequent doses (if second dose is tolerated); LV 400 mg/m2 (or equivalent levo-LV) over 120 minutes on Days 1 and 15.; Irinotecan 180 mg/m2 over 90 minutes (concurrently with the LV infusion) on Days 1 and 15.; 5-FU 400 mg/m2 bolus on Days 1 and 15.; 5-FU 2400 mg/m2 infusion over 46 hours on Days 1 and 15.	Drug: Leucovorin; Intravenous infusion; Other Names: LV; Folinic acid; Drug: Irinotecan; Intravenous infusion; Other Names: Campto; Camptosar; Biological: Bevacizumab; Intravenous infusion; Other Names: Avastin; Zirabev; Drug: 5-FU; Intravenous infusion; Other Names: 5-fluorouracil; 5FU; Fluorouracil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients achieving 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	Assessed from baseline to 30 days after last dose of study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients achieving a reduction in tumour volume	Objective response rate, defined as the percentage of patients achieving a complete or partial (30%+) response to treatment	Assessed from baseline to 30 days after last dose of study drug
Number of patients surviving	Overall survival, defined as the time from randomization to the time of death from any cause	Assessed from baseline to 30 days after last dose of study drug
Number of patients reporting treatment-emergent adverse events (TEAEs)	TEAEs assessed and graded by CTCAE v5.0	Assessed from baseline to 30 days after last dose of study drug

Collaborators and Investigators

• Sponsor: NuCana plc
• Investigators: Study Director: Elisabeth Oelmann, MD, PhD, NuCana plc

Study record dates

Study Major Dates

• Study Start (Actual): April 18, 2023
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: December 22, 2022
• First Submitted That Met QC Criteria: January 9, 2023
• First Posted (Actual): January 10, 2023

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Bevacizumab; Chemotherapy; Irinotecan; Metastatic cancer; Neoplasm; Leucovorin; 5-FU; Antineoplastic agents; Locally advanced cancer; Relapsed metastatic adenocarcinoma of colon/rectum; NUC-3373; Fosifloxuridine nafalbenamide; Second-line chemotherapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplasms; Colorectal Neoplasms; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Bevacizumab; Leucovorin; Irinotecan
• Other Study ID Numbers: NuTide:323; 2022-001459-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No