Clinical trial NCT05678257: A Study of NUC-3373 in Combination With Other Agents in Patients With Colorectal Cancer
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
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
Lead sponsor: NuCana plc
Sponsor class: OTHER
First posted: 2023-01-10
Enrollment: 182
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of patients achieving progress-free survival (PFS)
timeFrame: Assessed from baseline to 30 days after last dose of study drug
Secondary outcomes:
measure: Number of patients achieving a reduction in tumour volume
timeFrame: Assessed from baseline to 30 days after last dose of study drug
measure: Number of patients surviving
timeFrame: Assessed from baseline to 30 days after last dose of study drug
measure: Number of patients reporting treatment-emergent adverse events (TEAEs)
timeFrame: Assessed from baseline to 30 days after last dose of study drug
Other outcomes:
Locations:
city: Newark
country: United States
facility: Helen F. Graham Cancer Center
state: Delaware
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida Health Medical Oncology - Davis Cancer Pavilion
state: Florida
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Wichita
country: United States
facility: Cancer Center of Kansas
state: Kansas
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Worcester
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: Cincinnati
country: United States
facility: The Christ Hospital Cancer Center
state: Ohio
city: Dallas
country: United States
facility: Texas Oncology - Baylor Charles A. Sammons Cancer Center
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Tyler
country: United States
facility: USOR - Texas Oncology Northeast Texas
state: Texas
city: Kirkland
country: United States
facility: Fred Hutchinson Cancer Center at Evergreen Health
state: Washington
city: Vancouver
country: United States
facility: Northwest Cancer Specialists, P.C. dba Compass Oncology - Vancouver Cancer Center
state: Washington
city: Strasbourg
country: France
facility: Strasbourg Oncology Liberale - Clinique Sainte-Anne
state: Alsace
city: Marseille
country: France
facility: Hôpital Européen Marseille
state: Bouches-du-Rhône
city: Dijon
country: France
facility: Centre Georges-François Leclerc
state: Bourgogne-Franche-Comté
city: Besançon
country: France
facility: Centre Hospitalier Régional et Universitaire de Besançon - Hôpital Jean-Minjoz
state: Doubs
city: Bordeaux
country: France
facility: Institut Bergonié
state: Gironde
city: Poitiers
country: France
facility: Centre Hospitalier Universitaire de Poitiers
state: Vienne
city: Nantes
country: France
facility: Centre Hospitalier UniversitaireNantes - Hôtel Dieu
city: Paris
country: France
facility: Hôpital Européen Georges-Pompidou
state: Île-de-France
city: Suresnes
country: France
facility: Hôpital Foch
state: Île-de-France
city: München
country: Germany
facility: München Klinik Neuperlach
state: Bavaria
city: Frankfurt
country: Germany
facility: Krankenhaus Nordwest
state: Hesse
city: Ulm
country: Germany
facility: Universitätsklinik Ulm - Oberen Eselsberg
state: Tübingen
city: Berlin
country: Germany
facility: Charité Campus Virchow-Klinikum
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria - Università degli Studi della Campania Luigi Vanvitelli
state: Campania
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
state: Lombardia
city: Faenza
country: Italy
facility: Ospedale Santa Maria delle Croci di Ravenna
state: Ravenna
city: Firenze
country: Italy
facility: Azienda Ospedaliero Universitaria Careggi
state: Toscana
city: Padova
country: Italy
facility: Istituto Oncologico Veneto - IRCCS
state: Veneto
city: Ancona
country: Italy
facility: Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona
city: Milano
country: Italy
facility: Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda
city: Potenza
country: Italy
facility: Azienda Ospedaliera Regionale San Carlo
city: Badalona
country: Spain
facility: Institut Català d'Oncologia - ICO Badalona - Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: Santiago de Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago (CHUS)
state: La Coruña
city: Alcorcón
country: Spain
facility: Hospital Universitario Fundación Alcorcón
state: Madrid
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro
state: Madrid
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebrón
city: Barcelona
country: Spain
facility: Hospital Duran i Reynals
city: León
country: Spain
facility: Hospital de León
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: MD Anderson Cancer Center Madrid
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Romford
country: United Kingdom
facility: Queen's Hospital
state: Essex
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
state: Greater London
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust
state: Greater London
city: London
country: United Kingdom
facility: Guy's and Saint Thomas' NHS Foundation Trust
state: Greater London
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
state: Lancashire
city: Northwood
country: United Kingdom
facility: Mount Vernon Cancer Centre - East and North Hertfordshire NHS Trust
state: Middlesex
city: Cardiff
country: United Kingdom
facility: Velindre University NHS Trust
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde
Study officials:
affiliation: NuCana plc
name: Elisabeth Oelmann, MD, PhD
role: STUDY_DIRECTOR
References: