Efficacy of Post-Resection Chemotherapy with Irinotecan, Fluorouracil, and Oxaliplatin in Metastatic Colorectal Cancer: A Phase III Randomized Trial
- Trial ID
- 2024-512174-10-00
- Protocol
- FIRE-9 - PORT
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase III clinical trial is to compare the **efficacy** of active additive chemotherapy following definitive treatment of metastases with structured follow-up only in patients with **metastatic colorectal cancer**. This objective is clinically relevant as it aims to determine whether additional chemotherapy can improve outcomes in patients who have undergone resection or ablation of metastatic lesions, potentially influencing post-treatment management strategies for this patient population.
Participants
The clinical trial involves participants diagnosed with **metastatic colorectal cancer**. The study population includes both male and female subjects, aged 18 years and older, with a focus on individuals who have undergone definitive treatment of metastases. Participants are required to have a histologically confirmed adenocarcinoma of the colon or rectum, with resected or effectively treated metastases, and no radiographic evidence of active metastatic disease at study entry. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are fully active or capable of self-care. Adequate bone marrow, hepatic, and renal function are prerequisites, as defined by specific laboratory test results. The trial population was selected based on these criteria, and both genders are represented. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The trial does not exclude vulnerable populations, indicating inclusivity in the selection process.
Plans and Procedures
The clinical trial is a **prospective, randomized, open, multicenter Phase III trial** designed to evaluate the efficacy of active post-resection or ablation chemotherapy in patients with **metastatic colorectal cancer**. The primary objective is to compare the efficacy of active additive chemotherapy following definitive treatment of metastases to structured follow-up only. The trial is expected to conclude by December 31, 2030, with recruitment having commenced on November 11, 2021. Participants will be involved in the study for a maximum treatment period of 24 months.
The trial involves several key medications, including **irinotecan hydrochloride trihydrate**, **fluorouracil**, **oxaliplatin**, **capecitabine**, **disodium folinate**, and **calcium folinate pentahydrate**. These medications are administered via infusion or orally, depending on the specific drug. The study is structured to include an initial screening visit, where eligibility is confirmed based on criteria such as age, histological confirmation of adenocarcinoma, and adequate organ function. Following the screening, participants will be randomized to receive either the active chemotherapy regimen or structured follow-up.
Study visits are scheduled at regular intervals to monitor the participants' health status, treatment adherence, and any adverse events. The primary endpoint is progression-free survival at 24 months, defined as the time from randomization to death or evidence of disease progression. Follow-up visits will continue throughout the treatment period, with the end-of-study visit marking the conclusion of the participant's involvement. Conditions that may lead to early termination from the study include significant adverse reactions, withdrawal of consent, or any medical condition that contraindicates continued participation.
Treatment
The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy in patients with metastatic colorectal cancer. **Irinotecan Hydrochloride Trihydrate** is provided as a concentrate for solution for infusion. The maximum daily dose is 180 mg/m², with a total maximum dose of 2160 mg/m² over a treatment period of up to 24 weeks. The administration route is via infusion.
**Fluorouracil** is administered as a solution for injection or infusion. The maximum daily dose is 2400 mg/m², with a total maximum dose of 28800 mg/m² over the same treatment period. This medication is also delivered through infusion.
**Oxaliplatin** is provided as a solution for infusion, with a maximum daily dose of 130 mg/m² and a total maximum dose of 1040 mg/m² over 24 weeks. The administration is conducted via infusion.
**Capecitabine** is administered in the form of film-coated tablets. The maximum daily dose is 1000 mg/m², with a total maximum dose of 8000 mg/m² over the treatment period. This medication is taken orally.
**Disodium Folinate** is available as a solution for injection or infusion. The maximum daily dose is 400 mg/m², with a total maximum dose of 4800 mg/m² over 24 weeks. The administration route is infusion.
**Calcium Folinate Pentahydrate** is also provided as a solution for injection. The maximum daily dose is 400 mg/m², with a total maximum dose of 4800 mg/m² over the treatment period. This medication is administered via infusion.
All medications are of chemical origin and are not formulated for pediatric use. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial does not include any non-experimental treatments such as placebo or comparator treatments.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **Progression-free survival (PFS)** time at the 24-month follow-up. This endpoint is defined as the time from randomization to either death or evidence of disease progression, whichever occurs first. The trial is designed to compare the efficacy of active additive chemotherapy following definitive treatment of metastases against structured follow-up only in patients with metastatic colorectal cancer.
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 rectum
- Resected (R0 or R1) and/or effectively treated metastases (all techniques allowed) of colorectal cancer within 3-10 weeks before randomization (earlier randomisation allowed if at least 3 weeks interval between intervention and treatment start is guaranteed) AND resected primary tumor (synchronous or metachronous). In cases of synchronous metastases the interval of 3-10 weeks might be calculated following the removal of the primary tumor if this intervention was the last to address all tumor lesions
- Absence of significant active wound healing complications (if applicable) at randomization. Resolved wound healing complications after resection/ablation are acceptable for inclusion into the trial
- No radiographic evidence of active metastatic disease at study entry in a CT and/or MRI scan not older than 10 weeks prior randomization. Pre- surgery/ablation images are eligible for the study if all lesions have been addressed in the interval
- 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 (1500/µL) • Hemoglobin ≥ 80 g/L (8 g/dL) • Platelet count ≥ 100 x109/L (100000/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: a) Prior treatment with 5-FU or capecitabine without unusual toxicity or b) If tested, normal DPD deficiency test according to the standard of the study site or c) If tested, in patients with DPD deficiency test with a CPIC activity score of 1.0-1.5 fluoropyrimidine/capecitabine dosage should be reduced by 50%
- For women of childbearing potential (WOCBP): negative pregnancy test within 14 days before randomization 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 9 months after the last dose of Oxaliplatin or for at least 6 months after the last dose of all other 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
- Treatment of metastases greater than 3 cm with radio-frequency/microwave ablation within 24 months prior to study entry if applicable.
- Treatment of metastases greater than 5 cm with radiation (stereotactic/ brachytherapy) within 24 months prior to study entry if applicable.
- Any previous systemic therapy is allowed for inclusion into the trial. However, if previous oxaliplatin-containing chemotherapy at any time for metastatic or localized disease was carried out, the inclusion into the trial is permitted under the condition, that a) A total duration of oxaliplatin-based therapy of six months (i.e. 12 cycles of FOLFOX / FOLFOXIRI or 8 cycles CAPOX) is not exceeded - including therapy within the FIRE-9/PORT trial b) If already more than three months of oxaliplatin-based therapy (i.e. >6 cycles of FOLFOX / FOLFOXIRI or >4 cycles CAPOX) was used, the study therapy should be started with an irinotecan-based regimen (i.e. FOLFIRI or FOLFOXIRI) However, in the case of FOLFOXIRI therapy in the trial, the above mention regulation concerning the total dosing of oxaliplatin still applies (i.e. 12 cycles of FOLFOX / FOLFOXIRI or 8 cycles CAPOX should not be exceeded - including therapy within the FIRE-9/PORT trial).
- 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
- Active uncontrolled infection by investigator’s perspective.
- Severe chronic non-healing wounds, ulcerous lesions or untreated bone fracture.
- Known hypersensitivity to 5-FU, folinic acid irinotecan, oxaliplatin or capecitabine 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 2)).
- Inflammatory bowel disease and/or bowel obstruction.
- Simultaneous application of Johannis herbs preparations.
- Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency.
- Major surgical procedure, open biopsy, or significant traumatic injury within 21 days prior to randomization or at least to intended treatment start or anticipation of need for major surgical procedure during the course of the study or non-recovery from side effects of any such procedure.
- 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.
- Medical history of malignant disease other than mCRC 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% 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.
- Suspected SARS-CoV-2 infection with or without symptoms (evaluation according to local policy in respective center with respect to actual status of pandemic and with reference to the policy that would apply to patients with similar therapy outside the trial). This may include assessment of vaccination status, anamnesis, physical examination and potentially antigen and/or PCR testing.
- Patient committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
- Limited legal capacity.
- Concomitant administration of strong CYP3A4 and/or UGT1A1 inducers (e.g. Rifampicin, Carbamazepin, Phenobarbital, Phenytoin or Apalutamid).
- Planned inoculation/vaccination with a live vaccine during treatment with Oxaliplatin and/or Irinotecan, and until 6 months after treatment with Irinotecan
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 11 Nov 2021 | 507 |
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 |
|---|---|---|---|---|---|---|
DISODIUM FOLINATE | Test | — | INFUSION | 400 | 24 | SUB20566 |
OXALIPLATIN | Test | — | INFUSION | 130 | 24 | SUB09490MIG |
IRINOTECAN HYDROCHLORIDE TRIHYDRATE | Test | — | INFUSION | 180 | 24 | SUB45873 |
CALCIUM FOLINATE PENTAHYDRATE | Test | — | INFUSION | 400 | 24 | SUB76309 |
FLUOROURACIL | Test | — | INFUSION | 2400 | 24 | SUB07721MIG |
CAPECITABINE | Test | — | ORAL | 1000 | 24 | SUB12474MIG |