Relapsed, unresectable, histologically or cytologically confirmed metastatic adenocarcinoma of colon or rectum with radiologically measurable disease. MedDRA version: 27.0 Level: PT Classification code 10052358 Term: Colorectal cancer metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: NUC-3373 for infusion
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Fosifloxuridine nafalbenamide
CAS Number: 1332837-31-6
Current Sponsor code: NUC-337
CPF-373
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 125-
Product Name: 5-Fluorouracil
Pharmaceutical Form: Solution for infusion
INN or Proposed
Sponsors
NuCana plc
Eligibility
Sex/Gender
All
Inclusion 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 =65 years) yes F.1.3.1 Number of subjects for this age range 6
Exclusion criteria
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • To compare progression-free survival (PFS) of NUC-3373 in combination with leucovorin (LV), irinotecan and bevacizumab (NUFIRI-bev) with 5-fluorouracil (5-FU) in combination with LV, irinotecan and bevacizumab (FOLFIRI-bev) • To determine the optimal NUFIRI-bev dosing schedule;Secondary Objective: • To compare the efficacy of NUFIRI-bev to FOLFIRI-bev in terms of: o Objective response rate (ORR) o Duration of response (DoR) o Disease control rate (DCR) o Maximum percentage change in tumour size o Overall survival (OS) • To assess the safety and tolerability of NUFIRI-bev compared to FOLFIRI-bev • To assess the pharmacokinetics (PK) of NUFIRI-bev;Primary end point(s): PFS, 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;Timepoint(s) of evaluation of this end point: End of trial | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Efficacy • ORR, defined as the percentage of patients achieving a complete or partial response to treatment • DoR, defined as the time from initial clinical response (partial response [PR] or complete response [CR]) to the first observation of tumour progression or death from any cause • DCR, defined as the percentage of patients demonstrating a best overall response (BOR) of CR, PR or stable disease (SD) • Maximum percentage change from baseline in tumour size according to RECIST v1.1 • OS, defined as the time from randomisation to the time of death from any cause Safety Safety and tolerability will be assessed by evaluation of: • Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs; per Common Terminology Criteria for Adverse Events [CTCAE] v5.0) • Deaths due to TEAEs • Treatment modifications due to TEAEs • Clinically-significant laboratory changes (per CTCAE v5.0) • Electrocardiograms (ECGs) Pharmacokinetics The PK of the NUFIRI-bev regimen will be assessed, including: • Concentration at end of infusion (Cinf) • Maximum concentration (Cmax) • Area under the plasma concentration-time curve (AUC) • Half-life (t1/2) • Volume of distribution (Vd) • Clearance (CL) The analytes measured in plasma will include, but are not limited to: • NUC-3373, 5-FU, a-fluoro-ß-alanine (FBAL), deoxyuridine (dUrd), irinotecan, SN-38;Timepoint(s) of evaluation of this end point: End of trial | — |
Countries
France, Germany, Italy, Spain, United Kingdom, United States
Contacts
Public ContactNuCana Clinical Study Information
NuCana plc
Outcome results
None listed