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

Colorectal Cancer Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05678257
• Other study ID #: NuTide:323
• Secondary ID: 2022-001459-17
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: April 18, 2023
• Est. completion date: March 2025

Study information

• Verified date: March 2024
• Source: NuCana plc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 182
• Est. completion date: March 2025
• Est. primary completion date: September 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Adenocarcinoma
• Colorectal Adenocarcinoma
• Colorectal Cancer
• Colorectal Cancer Metastatic
• Colorectal Neoplasms
• Neoplasm, Colorectal
• Neoplasms

Intervention

Drug:
• Fosifloxuridine Nafalbenamide
Intravenous infusion
• Leucovorin
Intravenous infusion
• Irinotecan
Intravenous infusion

Biological:
• Bevacizumab
Intravenous infusion

Drug:
• 5-FU
Intravenous infusion

Locations

Country	Name	City	State
France	Centre Hospitalier Régional et Universitaire de Besançon - Hôpital Jean-Minjoz	Besançon	Doubs
France	Institut Bergonié	Bordeaux	Gironde
France	Centre Georges-François Leclerc	Dijon	Bourgogne-Franche-Comté
France	Hôpital Européen Marseille	Marseille	Bouches-du-Rhône
France	Centre Hospitalier UniversitaireNantes - Hôtel Dieu	Nantes
France	Hôpital Européen Georges-Pompidou	Paris	Île-de-France
France	Centre Hospitalier Universitaire de Poitiers	Poitiers	Vienne
France	Strasbourg Oncology Liberale - Clinique Sainte-Anne	Strasbourg	Alsace
France	Hôpital Foch	Suresnes	Île-de-France
Germany	Charité Campus Virchow-Klinikum	Berlin
Germany	Krankenhaus Nordwest	Frankfurt	Hesse
Germany	München Klinik Neuperlach	München	Bavaria
Germany	Universitätsklinik Ulm - Oberen Eselsberg	Ulm	Tübingen
Italy	Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona	Ancona
Italy	Ospedale Santa Maria delle Croci di Ravenna	Faenza	Ravenna
Italy	Azienda Ospedaliero Universitaria Careggi	Firenze	Toscana
Italy	Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda	Milano
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano	Lombardia
Italy	Azienda Ospedaliera Universitaria - Università degli Studi della Campania Luigi Vanvitelli	Napoli	Campania
Italy	Istituto Oncologico Veneto - IRCCS	Padova	Veneto
Italy	Azienda Ospedaliera Regionale San Carlo	Potenza
Spain	Hospital Universitario Fundación Alcorcón	Alcorcón	Madrid
Spain	Institut Català d'Oncologia - ICO Badalona - Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Duran i Reynals	Barcelona
Spain	Hospital Universitari Vall d'Hebrón	Barcelona
Spain	Hospital de León	León
Spain	Hospital Universitari Arnau de Vilanova	Lleida
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	MD Anderson Cancer Center Madrid	Madrid
Spain	Hospital Universitario Puerta de Hierro	Majadahonda	Madrid
Spain	Hospital Universitario Virgen de la Victoria	Málaga
Spain	Complejo Hospitalario Universitario de Santiago (CHUS)	Santiago de Compostela	La Coruña
Spain	Hospital Universitario Virgen del Rocío	Sevilla
United Kingdom	Velindre University NHS Trust	Cardiff
United Kingdom	NHS Greater Glasgow and Clyde	Glasgow
United Kingdom	Guy's and Saint Thomas' NHS Foundation Trust	London	Greater London
United Kingdom	Royal Free London NHS Foundation Trust	London	Greater London
United Kingdom	University College London Hospitals NHS Foundation Trust	London	Greater London
United Kingdom	The Christie NHS Foundation Trust	Manchester	Lancashire
United Kingdom	Mount Vernon Cancer Centre - East and North Hertfordshire NHS Trust	Northwood	Middlesex
United Kingdom	Queen's Hospital	Romford	Essex
United States	Boston Medical Center	Boston	Massachusetts
United States	The Christ Hospital Cancer Center	Cincinnati	Ohio
United States	Texas Oncology - Baylor Charles A. Sammons Cancer Center	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	University of Florida Health Medical Oncology - Davis Cancer Pavilion	Gainesville	Florida
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	Fred Hutchinson Cancer Center at Evergreen Health	Kirkland	Washington
United States	Norton Cancer Institute	Louisville	Kentucky
United States	Morristown Medical Center	Morristown	New Jersey
United States	Helen F. Graham Cancer Center	Newark	Delaware
United States	USOR - Texas Oncology Northeast Texas	Tyler	Texas
United States	Northwest Cancer Specialists, P.C. dba Compass Oncology - Vancouver Cancer Center	Vancouver	Washington
United States	Georgetown University Medical Center	Washington	District of Columbia
United States	Cancer Center of Kansas	Wichita	Kansas
United States	University of Massachusetts Worcester	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
NuCana plc

Countries where clinical trial is conducted

United States,  France,  Germany,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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