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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Colorectal Cancer, Colorectal Neoplasms, Colorectal Adenocarcinoma, Colorectal Cancer Metastatic, Neoplasm, Colorectal

Intervention / Treatment
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* Drug: Fosifloxuridine Nafalbenamide
* Drug: Leucovorin
* Drug: Irinotecan
* Biological: Bevacizumab
* Drug: 5-FU


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of written informed consent. Histological or cytological confirmation of colorectal adenocarcinoma (excluding appendiceal and anal canal cancers, as well as colorectal cancers of mixed histologies [e.g., mucinous adenocarcinoma, micropapillary, signet-ring cell carcinoma]) that is unresectable and/or 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 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. Known RAS and BRAF status. Patients with wild-type KRAS 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. 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. Adequate liver function, as defined by: serum total bilirubin ≤1.5×upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN (or ≤5×ULN if liver metastases are present). Adequate renal function assessed as serum creatinine <1.5×ULN or 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 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 or to use two highly effective forms of contraception, one of which must be a barrier method. 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. Patients must have been advised to take measures to avoid or minimize exposure to UV light for the duration of study participation and for a period of 4 weeks following the last dose of study medication. Exclusion Criteria: Hypersensitivity or current contra-indications to 5-FU, FUDR, or capecitabine. 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 (super refined polysorbate 80 [SRP80], dimethylacetamide [DMA]). Symptomatic 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: For nitrosoureas and mitomycin C within 6 weeks of first administration of study treatment Corticosteroid treatment is allowed during screening but should be weaned to a dose of ≤10 mg prednisolone (or steroid equivalent) by Cycle 1 Day 1 * Palliative radiotherapy during participation in the study is permitted, but should not be concurrent with study treatment and recovery should be allowed to prevent overlapping toxicity (refer to Section 10.4). It should not include a target lesion. 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, including the following: Congestive heart failure (New York Heart Association Class III or Class IV) Clinically significant coronary heart disease or myocardial infarction within 6 months of the first dose of study medication or high risk of uncontrolled arrhythmia Unstable or poorly controlled angina pectoris Complete left bundle branch, fascicular block or other clinically significant abnormal ECG finding QTc interval >470 milliseconds History of or current risk factor for torsade de pointes (e.g., heart failure, hypokalaemia, or a family history of long QT syndrome) History of severe skin reactions History of severe ocular disorders Interstitial pneumonitis or pulmonary fibrosis Any condition (e.g., known or suspected poor compliance, psychological instability, geographical location, etc.) that, in the judgment of the Investigator, may affect the patient's ability to provide informed consent and undergo study procedures. Patients with a history of haemoptysis (1/2 teaspoon or more of red blood) within 6 months prior to enrolment. Wound healing complications or surgery within 28 days of starting bevacizumab (wound healing must have been fully completed before starting bevacizumab). Unhealed wound, active gastric or duodenal ulcer, or bone fracture. Thromboembolic event in the 6 months before inclusion (e.g., transitory ischemic stroke, stroke, subarachnoid haemorrhage) except peripheral deep vein thrombosis treated with anticoagulants. Known inherited or acquired bleeding disorders. 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. Uncontrolled hypertension. Severe proteinuria (nephrotic syndrome). Acute intestinal obstruction or sub-obstruction, history of inflammatory intestinal disease or extended resection of the small intestine. Presence of a colic prosthesis. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NUFIRI-bev on a Q1W NUC-3373 schedule<br>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 dose 60 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<br>* Intravenous infusion<br>* Other names: Nucleotide analogue;Drug: Leucovorin<br>* Intravenous infusion<br>* Other names: LV;Drug: Irinotecan<br>* Intravenous infusion<br>* Other names: Camptosar;Biological: Bevacizumab<br>* Intravenous infusion<br>* Other names: Zirabev;|
| Experimental: NUFIRI-bev on a Q2W NUC-3373 schedule<br>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 dose 60 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<br>* Intravenous infusion<br>* Other names: Nucleotide analogue;Drug: Leucovorin<br>* Intravenous infusion<br>* Other names: LV;Drug: Irinotecan<br>* Intravenous infusion<br>* Other names: Camptosar;Biological: Bevacizumab<br>* Intravenous infusion<br>* Other names: Zirabev;|
| Active Comparator: FOLFIRI-bev on a Q2W schedule<br>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 dose 60 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<br>* Intravenous infusion<br>* Other names: LV;Drug: Irinotecan<br>* Intravenous infusion<br>* Other names: Camptosar;Biological: Bevacizumab<br>* Intravenous infusion<br>* Other names: Zirabev;Drug: 5-FU<br>* Intravenous infusion<br>* Other names: Fluorouracil;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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