Fluorouracil Treatment Via Colon for Colorectal Cancer

Official title

Fluorouracil Treatment Via Colon for Colorectal Cancer: an Exploratory Study

Overview

Fluorouracil (5-FU) is a commonly used drug for colorectal cancer (CRC). Thermosensitive hydrogel presents a promising carrier for 5-FU to address challenges encountered with traditional administration methods. We propose an integrated approach utilizing colonic transendoscopic enteral tubing to cover the entire colon flexibly, coupled with a thermo-sensitive gel to enhance the adhesion of 5-FU. This clinical trial aims to assess the feasibility, safety, and efficacy of this approach for treating CRC.

Interventions

• Drug Colonic local administration of fluorouracil with enhanced adhesion
  Fluorouracil is administered via the colon as an injectable solution at a dose of 500 mg per day for 6 days, along with poloxamer 407 and poloxamer 188 used as thermosensitive hydrogel to enhance adhesion.

Primary outcome measures

• Objective response rate (according to RECIST1.1, investigator assessment) [Time frame: One, three, and six months (or until conversion to surgery) after the initial treatment]

Secondary outcome measures (7)

• Progression-free survival [Time frame: One, three, and six months (or until conversion to surgery) after the initial treatment]
• Overall survival [Time frame: Every 3 months up to 24 months after the end of treatment]
• Disease control rate (according to RECIST1.1, investigator assessment) [Time frame: One, three, and six months (or before conversion to surgery) after the initial treatment]
• Drop period to ensure operation resection [Time frame: Time from the first treatment to 4-6 cycles (each cycle is 28 days) of treatment]
• Converted resection rate [Time frame: Time from the first treatment to 4-6 cycles (each cycle is 28 days) of treatment]
• Actual R0 resection rate [Time frame: Time from the first treatment to 4-6 cycles (each cycle is 28 days) of treatment]
• The incidence of treatment-related adverse events (AE) assessed by CTCAE, Version 5.0 [Time frame: Throughout the treatment period and continuing for an additional 6 months after the treatment concludes, an average of 1 year]

Eligibility criteria

Inclusion criteria

• Chinese individuals aged 18 to 75 years, both male and female;
• Histologically confirmed diagnosis of colorectal cancer with measurable primary lesion according to RECIST 1.1;
• ECOG performance status ≤2;
• Expected survival of more than 3 months;
• Multidisciplinary team consensus that the patient is suitable for adding local chemotherapy to the established tumor treatment regimen;
• Adequate organ function meeting the following criteria: (1) Absolute neutrophil count ≥1.5 × 10\^9/L, platelets ≥100 × 10\^9/L, hemoglobin ≥90 g/L; (2) Total bilirubin ≤1.5 times the upper limit of normal (patients with biliary drainage via retrograde techniques included); ALT and AST ≤5 times the upper limit of normal, and for patients with liver metastases, serum total bilirubin less than or equal to 3 times the upper limit of the normal reference range; (3) Creatinine <120 μmol/L, or MDRD estimated glomerular filtration rate >60 mL/min; (4) Doppler echocardiography assessment: Left ventricular ejection fraction (LVEF) ≥50%;
• Women of childbearing potential must have a negative pregnancy test (serum or urine) within 7 days before enrollment, and sexually active men or women agree to use appropriate contraception during the trial and for 8 weeks after the last dose of investigational drug;
• Suitable physical condition and personal willingness to undergo colonic transendoscopic enteral tubing;
• Willingness to cooperate with physicians, and agree to regular follow-up visits and examinations as recommended after completion of treatment;
• Agreement to specimen collection and voluntary signing of a written informed consent form.

Exclusion criteria

• Uncontrolled cardiovascular diseases, such as congestive heart failure (NYHA III-IV), coronary artery disease, cardiomyopathy, arrhythmias, or hemodynamic instability at enrollment, with a risk of significant events during the treatment period;
• Active severe clinical infections (≥ Grade 2 according to NCI-CTCAE version 5.0), including fungal, viral, or tuberculosis infections within the gastrointestinal tract;
• Coagulation abnormalities with bleeding tendencies (who do not meet the criteria of having a normal INR without the use of anticoagulants within 14 days prior to enrollment). Participants receiving anticoagulants or vitamin K antagonists such as warfarin or heparin are excluded unless their international normalized ratio (INR) is ≤1.5, with allowance for low-dose warfarin (1 mg orally once daily) or low-dose aspirin (daily dose not exceeding 100 mg) for prophylaxis;
• History of immunodeficiency or other acquired or congenital immunodeficiency diseases, or history of organ transplantation;
• Known progressive or actively treated other malignancies requiring intervention, except for adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or cervical carcinoma in situ;
• Presence of other serious diseases that would render the subject ineligible for enrollment as determined by the investigator;
• Breastfeeding women;
• Known allergy or intolerance to the investigational drug or its excipients;
• Participation in another drug clinical trial within the past four weeks;
• Lack of legal capacity or restricted legal capacity.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• The Second Affiliated Hospital of Nanjing Medical University — Nanjing

Publications

• Sun W, Zhang N, Li A, Zou W, Xu W. Preparation and evaluation of N(3)-O-toluyl-fluorouracil-loaded liposomes. Int J Pharm. 2008 Apr 2;353(1-2):243-50. doi: 10.1016/j.ijpharm.2007.11.017. Epub 2007 Nov 17. PMID 18155370
• Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003 May;3(5):330-8. doi: 10.1038/nrc1074. PMID 12724731
• Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol. 1997 Jan;15(1):110-5. doi: 10.1200/JCO.1997.15.1.110. PMID 8996131
• Galandiuk S, Wrightson W, Marr L, Myers S, LaRocca RV. Suppository delivery of 5-fluorouracil in rectal cancer. Ann Surg Oncol. 1996 May;3(3):270-6. doi: 10.1007/BF02306282. PMID 8726182
• Kulkarni R, Fanse S, Burgess DJ. Mucoadhesive drug delivery systems: a promising noninvasive approach to bioavailability enhancement. Part II: formulation considerations. Expert Opin Drug Deliv. 2023 Mar;20(3):413-434. doi: 10.1080/17425247.2023.2181332. Epub 2023 Feb 22. PMID 36803264
• Zarrintaj P, Ramsey JD, Samadi A, Atoufi Z, Yazdi MK, Ganjali MR, Amirabad LM, Zangene E, Farokhi M, Formela K, Saeb MR, Mozafari M, Thomas S. Poloxamer: A versatile tri-block copolymer for biomedical applications. Acta Biomater. 2020 Jul 1;110:37-67. doi: 10.1016/j.actbio.2020.04.028. Epub 2020 May 15. PMID 32417265
• Al Sabbagh C, Seguin J, Agapova E, Kramerich D, Boudy V, Mignet N. Thermosensitive hydrogels for local delivery of 5-fluorouracil as neoadjuvant or adjuvant therapy in colorectal cancer. Eur J Pharm Biopharm. 2020 Dec;157:154-164. doi: 10.1016/j.ejpb.2020.10.011. Epub 2020 Oct 22. PMID 33222768
• Seguin J, Pimpie C, Roy P, Al Sabbagh C, Pocard M, Mignet N, Boudy V. Combination of tumor cell anti-adhesion and anti-tumor effect to prevent recurrence after cytoreductive surgery in a mice model. Eur J Pharm Biopharm. 2021 Dec;169:37-43. doi: 10.1016/j.ejpb.2021.01.020. Epub 2021 Mar 14. PMID 33727143

Identifiers

NCT: NCT06385418 · WST-CRC-202404

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗