Fluorouracil Treatment Via Colon for Colorectal Cancer

Fluorouracil Treatment Via Colon for Colorectal Cancer: an Exploratory Study

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.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Colonic local administration of fluorouracil with enhanced adhesion

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Faming Zhang, MD, PhD; Phone Number: 86-025-58509883; Email: fzhang@njmu.edu.cn

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210011
      • Recruiting
      • The Second Affiliated Hospital of Nanjing Medical University
      • Contact: Faming Zhang, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Chinese individuals aged 18 to 75 years, both male and female;
2. Histologically confirmed diagnosis of colorectal cancer with measurable primary lesion according to RECIST 1.1;
3. ECOG performance status ≤2;
4. Expected survival of more than 3 months;
5. Multidisciplinary team consensus that the patient is suitable for adding local chemotherapy to the established tumor treatment regimen;
6. 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%;
7. 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;
8. Suitable physical condition and personal willingness to undergo colonic transendoscopic enteral tubing;
9. Willingness to cooperate with physicians, and agree to regular follow-up visits and examinations as recommended after completion of treatment;
10. Agreement to specimen collection and voluntary signing of a written informed consent form.

Exclusion Criteria:

1. 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;
2. Active severe clinical infections (≥ Grade 2 according to NCI-CTCAE version 5.0), including fungal, viral, or tuberculosis infections within the gastrointestinal tract;
3. 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;
4. History of immunodeficiency or other acquired or congenital immunodeficiency diseases, or history of organ transplantation;
5. 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;
6. Presence of other serious diseases that would render the subject ineligible for enrollment as determined by the investigator;
7. Breastfeeding women;
8. Known allergy or intolerance to the investigational drug or its excipients;
9. Participation in another drug clinical trial within the past four weeks;
10. Lack of legal capacity or restricted legal capacity.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (according to RECIST1.1, investigator assessment)	Objective response rate (ORR) is defined as complete response (CR) and partial response (PR) proportion of participants.	One, three, and six months (or until conversion to surgery) after the initial treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Progression-free survival (PFS) is defined as the time from the first initiation of study regimen treatment to the first imaging disease progression or the time of death, whichever occurs first.	One, three, and six months (or until conversion to surgery) after the initial treatment
Overall survival	Overall survival (OS) is defined as the time from the first initiation of the study regimen to death from any cause time.	Every 3 months up to 24 months after the end of treatment
Disease control rate (according to RECIST1.1, investigator assessment)	Disease control rate (DCR) is defined as the proportion of participants with complete response (CR), partial response (PR) and stable disease (SD) × 100%.	One, three, and six months (or before conversion to surgery) after the initial treatment
Drop period to ensure operation resection	Drop period to ensure operation resection is defined as the proportion of participants whose tumors shrink following study induction therapy, thereby enhancing the safety and feasibility of surgical removal.	Time from the first treatment to 4-6 cycles (each cycle is 28 days) of treatment
Converted resection rate	Surgical conversion rate, defined as the proportion of participants who achieved gross complete resection after 4-6 courses of study induction therapy.	Time from the first treatment to 4-6 cycles (each cycle is 28 days) of treatment
Actual R0 resection rate	Actual R0 resection rate is defined as the proportion of participants who achieved R0 surgical resection after 4-6 courses of study induction therapy.	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	The severity of AE was graded as mild (grade 1), moderate (grade 2), severe/disabling (grade 3), life threatening (grade 4), and death (grade 5). All AE were divided in definitely, probably and possibly related to treatment.	Throughout the treatment period and continuing for an additional 6 months after the treatment concludes, an average of 1 year

Collaborators and Investigators

• Sponsor: The Second Hospital of Nanjing Medical University
• Investigators: Principal Investigator: Faming Zhang, MD, PhD, Department of Microbiota Medicine & Medical Center for Digestive Diseases

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Zhang F, Lu G, Wang X, Wu L, Li R, Nie Y. Concept, breakthrough, and future of colonic transendoscopic enteral tubing. Chin Med J (Engl). 2024 Mar 20;137(6):633-635. doi: 10.1097/CM9.0000000000003020. Epub 2024 Feb 7. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2024
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): May 1, 2029

Study Registration Dates

• First Submitted: April 17, 2024
• First Submitted That Met QC Criteria: April 25, 2024
• First Posted (Actual): April 26, 2024

Study Record Updates

• Last Update Posted (Actual): June 26, 2024
• Last Update Submitted That Met QC Criteria: June 25, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Fluorouracil; Colorectal Cancer; Transendoscopic enteral tubing; Thermosensitive hydrogel
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Fluorouracil
• Other Study ID Numbers: WST-CRC-202404

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No