Phase III Trial on Preoperative Chemotherapy with Irinotecan, Oxaliplatin, and Capecitabine in Resectable Advanced Colon Cancer
- Trial ID
- 2023-508076-11-00
- Protocol
- PROTECTOR/FIRE-10
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase III trial is to compare the **efficacy** of preoperative chemotherapy before surgery to surgery followed by stage-guided adjuvant therapy in patients with advanced colon cancer. This study focuses on individuals with colon cancer staged T3-4 and/or nodal positive as determined by CT and/or MRI scan, without distant metastases. The clinical relevance of this objective lies in determining whether preoperative systemic therapy can improve surgical outcomes and potentially enhance overall survival rates in this patient population.
Participants
The clinical trial involves participants diagnosed with **colon cancer** staged T3-4 and/or nodal positive, as determined by CT and/or MRI scans, without distant metastases. The study population includes both male and female subjects, aged 18 years and older, with a histologically confirmed adenocarcinoma of the colon or upper rectum. Participants are required to have an ECOG performance status of 0-2, indicating they are fully active or capable of self-care. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria emphasize adequate bone marrow, hepatic, and renal function, as well as proficient fluorouracil metabolism. Lifestyle considerations such as diet and physical activity are not detailed in the available data. The trial includes a vulnerable population, and participants must have the intent for curative surgery with predicted T3 or T4 stage and/or nodal positivity. The absence of significant active wound healing and clear distant metastases is also required for inclusion. The sponsor has not provided specific details on the selection process or the total number of participants.
Plans and Procedures
The clinical trial is a **randomized**, open-label, multicenter Phase III study designed to evaluate the efficacy of preoperative systemic therapy in patients with advanced **colon cancer**. The trial aims to compare the outcomes of preoperative chemotherapy followed by surgery against surgery followed by stage-guided adjuvant therapy. The study will involve the administration of several chemotherapeutic agents, including **irinotecan**, **oxaliplatin**, **capecitabine**, **fluorouracil**, **disodium folinate**, and **calcium folinate**. These agents will be administered either via **infusion** or orally, depending on the specific medication.
The trial is expected to commence recruitment in December 2024 and is estimated to conclude by December 2034. Participants will be involved in the study for a maximum treatment period of 24 months. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess the primary endpoint of **disease-free survival**. The inclusion criteria require participants to have histologically confirmed adenocarcinoma of the colon or upper rectum, proficient **fluorouracil** metabolism, and adequate organ function, among other requirements. Participants must also be at least 18 years old and have an ECOG performance status of 0-2.
Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it in the participant's best interest. The primary endpoint of the study is disease-free survival, defined as the absence of surgery, resection, incomplete resection, disease recurrence, or death from any cause from the time of randomization. The trial's design and methodology are structured to ensure rigorous evaluation of the treatment's efficacy while maintaining participant safety and data integrity.
Treatment
The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy in the treatment of advanced colon cancer. **Irinotecan** is administered as a **solution for infusion**. The dosage is calculated based on body surface area, with a maximum daily dose of 150 mg/m² and a maximum total dose of 1800 mg/m² over a treatment period of 24 weeks. The route of administration is via infusion, and the formulation is not pediatric-specific.
**Oxaliplatin** is also provided as a **solution for infusion**. The dosing regimen involves a maximum daily dose of 130 mg/m² and a total dose not exceeding 1040 mg/m² over the same 24-week period. This medication is administered through infusion, and it is not formulated for pediatric use.
**Capecitabine** is administered in the form of **film-coated tablets**. The oral route is utilized for this medication, with a maximum daily dose of 1000 mg/m² and a cumulative dose of 8000 mg/m² over 24 weeks. This formulation is intended for adult patients only.
**Fluorouracil** is delivered as a **solution for injection/infusion**. The maximum daily dose is set at 2400 mg/m², with a total dose limit of 28800 mg/m² over the course of the trial. Administration is via infusion, and the formulation is not suitable for pediatric patients.
**Disodium folinate** is provided as a **solution for injection/infusion**. The dosing schedule allows for a maximum daily dose of 400 mg/m² and a total dose of 4800 mg/m² over 24 weeks. This medication is administered through infusion and is not designed for pediatric use.
**Calcium folinate** is similarly administered as a **solution for injection/infusion**. The maximum daily dose is 400 mg/m², with a total dose of 4800 mg/m² over the trial period. The route of administration is infusion, and the formulation is not pediatric-specific.
All medications are of chemical origin and are administered according to the specified dosing schedules. Participant compliance is monitored throughout the trial to ensure adherence to the treatment regimen. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this trial.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **disease-free survival (DFS)**. This endpoint is defined as the period during which patients experience no surgery, no resection, incomplete resection, disease recurrence (new metastases or local relapse), and death from any cause, starting from the time of randomization. In cases where no surgery, no resection, or incomplete resection occurs, the event timepoint will be set to two weeks post-randomization to prevent time-bias favoring the experimental or neoadjuvant therapy arm.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient’s signed informed consent.
- Patient’s age ≥18 years at the time of signing the informed consent.
- Histologically confirmed adenocarcinoma of the colon or upper rectum.
- Confirmed mismatch-repair proficient and/or microsatellite stable tumor. Both Immunohistochemistry and PCR can be used for diagnosis.
- Intent for curative surgery
- Predicted T3 or T4 stage and or nodal positivity (N+) in a computed tomography and/or magnetic resonance imaging scan of the abdomen/pelvis as assessed by the local study team. • T3-4 defined as invasion of surrounding tissue structures or organs • N+ defined as regional lymph node(s) without fat hilus and short axis diameter of ≥1 cm
- Absence of clear distant metastases assessed by the investigator based on respective routine evaluations within 6 weeks prior to inclusion into the trial (preferred: computed tomography of thorax and abdomen. Alternatively magnetic resonance images, sonography and x-rays might be used for assessment).
- Absence of significant active wound healing including severe chronic non-healing wounds, ulcerous lesions or untreated bone fracture.
- ECOG performance status 0-2.
- Adequate bone marrow, hepatic and renal organ function, defined by the following laboratory test results: • Absolute neutrophil count 1.5 x 109/L (1,500/µL) • Hemoglobin ≥ 80 g/L (8 g/dL) with or without transfusion • Platelet count ≥ 100 x109/L (100,000/µL) without transfusion • Total serum bilirubin of ≤ 1.5 x upper limit of normal (ULN) • Aspartate aminotransferase (AST/GOT) ≤ 3.0 × ULN. • Calculated glomerular filtration rate (GFR) according to Cockcroft-Gault formula or according to MDRD ≥ 50 mL/min or serum creatinine ≤ 1.5 x ULN
- Patients without anticoagulation need to present with an INR < 1.5 x ULN and PTT < 1.5 x ULN. Patient with prophylactic or therapeutic anticoagulation are allowed into the trial.
- Proficient fluorouracil metabolism as defined: Prior treatment with 5-FU or capecitabine without unusal toxicity or If tested, normal DPD deficiency test according to the standard of the study site or If tested, in patients with DPD deficiency test with a CPIC activity score of 1.0-1.5 fluoropyrimidine dosage should be reduced by 50% and patients are allowed into the trial.
- For women of childbearing potential (WOCBP): negative pregnancy test within 7 days before treatment initiation and agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of study treatment. A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male partner’s sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. For men: With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 6 months after the last dose of study treatment. Men must refrain from donating sperm during this same period. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 6 months after the last dose of study medication to avoid exposing the embryo.
Exclusion Criteria
- Ileus or directly imminent ileus as assessed by the local study team. Patients with treated and resolved ileus are allowed into the trial.
- Previous chemotherapy for colorectal cancer of any stage
- New York Heart Association Class III or greater heart failure by clinical judgement.
- Myocardial infarction within 6 months prior to randomization; percutaneous transluminal coronary angioplasty (PTCA) with or without stenting within 6 months prior to randomization.
- Unstable angina pectoris.
- Unstable cardiac arrhythmia > grade 2 NCI CTCAE despite anti-arrhythmic therapy.
- Ongoing toxicities > grade 2 NCI CTCAE, in particular peripheral neuropathy.
- Active uncontrolled infection by investigator’s perspective.
- Known hypersensitivity to 5-FU, folinic acid, capecitabine, irinotecan or oxaliplatin or to any of the other excipients listed in section 6.1 of the corresponding SmPC.
- Recent or concomitant treatment with brivudine.
- Peripheral sensitive neuropathy with functional impairment (> grade 1 acc. to CTCAE version 5.0 (see appendix)).
- Simultaneous application of St. John’s Wort preparations.
- Pernicious or other megaloblastic anemia caused by vitamin B12 deficiency.
- Major surgical procedure, open biopsy, or significant traumatic injury within 21 days prior to randomization that may interfere with systemic therapy as judged by the investigator.
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications., including but not limited to: - Simultaneous application of live vaccines during treatment with irinotecan and for at least 6 months after the last dose. - 5-FU must not be given in combination with brivudin, sorivudin and analogues to patients homozygous for DPD and patients known with completely missing DPD activity. - Severe diarrhoea.
- Medical history of malignant disease other than colorectal cancer with the following exceptions: - patients who have been disease-free for at least three years before randomization - patients with adequately treated and completely resected basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer, stage I uterine cancer - patients with any treated or untreated malignant disease that is associated with a 5-year survival prognosis of ≥ 90% at the time of inclusion (assessed and documented by the investigator) and does not require active therapy
- Known alcohol or drug abuse.
- Pregnant or breastfeeding females.
- Participation in a clinical trial or experimental drug treatment within 28 days prior to potential inclusion in the clinical trial or within a period of 5 half-lives of the substances administered in a clinical trial or during an experimental drug treatment prior to potential inclusion in the clinical trial, depending on which period is longest, or simultaneous participation in another clinical trial while taking part in this clinical trial.
- Patients depended on Sponsor, investigator or study site.
- Patient committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
- Limited legal capacity.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 01 Dec 2024 | 714 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
OXALIPLATIN | Test | — | INFUSION | 130 | 24 | SUB09490MIG |
CALCIUM FOLINATE | Test | — | INFUSION | 400 | 24 | SUB06052MIG |
IRINOTECAN | Test | — | INFUSION | 150 | 24 | SUB08295MIG |
FLUOROURACIL | Test | — | INFUSION | 2400 | 24 | SUB07721MIG |
CAPECITABINE | Test | — | ORAL | 1000 | 24 | SUB12474MIG |
DISODIUM FOLINATE | Test | — | INFUSION | 400 | 24 | SUB20566 |