Evaluation of Hepatic Arterial Infusion of Floxuridine with Systemic Therapy in Unresectable Colorectal Liver Metastases: A Randomized Controlled Trial
- Trial ID
- 2023-506194-35-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate whether the combination of **hepatic arterial infusion pump** (HAIP) chemotherapy and systemic therapy (HAIP-SYST) extends overall survival in chemo-naive patients with initially unresectable **colorectal liver metastases** compared to systemic therapy alone. This is clinically relevant as it may offer a more effective treatment option for patients with limited therapeutic alternatives, potentially improving survival outcomes.
Secondary objectives include:
- Investigating whether HAIP-SYST prolongs progression-free survival in the same patient population compared to systemic therapy alone.
- Assessing the local effect of adding HAIP therapy to the liver in terms of hepatic disease progression.
- Evaluating the impact of HAIP-SYST on the likelihood of patients undergoing subsequent local treatment versus systemic therapy alone.
- Examining the anti-tumor effect of HAIP-SYST compared to systemic therapy alone.
- Assessing additional surgical morbidity in patients who underwent HAIP placement and/or any tumor-related surgery.
- Evaluating the toxicity of HAIP-SYST versus systemic therapy alone.
- Comparing the Quality of Life (QoL) of patients treated with HAIP-SYST versus systemic therapy alone.
- Comparing the cost-effectiveness of induction treatment with HAIP-SYST versus systemic therapy alone.
Participants
The clinical trial involves participants diagnosed with **colorectal liver metastases**, focusing on individuals who are chemo-naive with initially unresectable conditions. The study population includes both male and female subjects aged 18 years and older, with no specific upper age limit indicated. Participants are required to have a primary tumor that is in situ and resectable without the need for neoadjuvant therapy, and they must be eligible for surgery and doublet chemotherapy. The trial does not include a vulnerable population. Participants must meet specific laboratory criteria, including adequate bone marrow, liver, and renal function, and must have an ECOG performance status of 0 or 1. The trial excludes individuals with extrahepatic metastases, except for those with small lesions not clearly suspicious of metastases. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified as part of the trial's considerations. Key inclusion criteria include a histologically confirmed diagnosis of colorectal adenocarcinoma and the technical feasibility of catheter positioning for HAIP chemotherapy. Participants must have a life expectancy of at least 12 weeks and known mutation status of RAS and BRAFV600E. The trial does not involve individuals with celiac trunk stenosis or those with both a replaced right and replaced left hepatic artery.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of hepatic arterial infusion pump chemotherapy combined with systemic therapy versus systemic therapy alone in patients with initially unresectable **colorectal liver metastases**. This is a randomized, controlled, double-blind trial with an estimated duration extending until December 2034. The trial aims to assess whether the combination therapy prolongs overall survival compared to systemic therapy alone. Participants will be randomly assigned to either the experimental group receiving the combination therapy or the control group receiving only systemic therapy.
The trial will involve multiple study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, laboratory values, and imaging results. Participants must have a histologically confirmed diagnosis of colorectal adenocarcinoma with unresectable liver metastases and no extrahepatic metastases. The screening visit will also include obtaining informed consent according to ICH/GCP guidelines. Following the inclusion visit, participants will undergo regular follow-up visits to monitor treatment response, adverse events, and overall health status. These visits will include assessments of progression-free survival, hepatic progression-free survival, and other secondary endpoints such as quality of life and surgical complication rates.
The expected length of participant involvement is up to 52 weeks, with the possibility of early termination if significant adverse events occur or if the participant's condition worsens. The end-of-study visit will conclude the trial for each participant, during which final assessments will be conducted to evaluate the primary and secondary endpoints. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.
Treatment
The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. **Irinotecan hydrochloride** is administered intravenously in a pharmaceutical form coded as PHF00230MIG. The maximum daily dose is 180 mg/m², with a total maximum dose of 4680 mg/m² over a treatment period of up to 52 weeks. This medication is classified as an antineoplastic antimetabolite.
**Heparin** is used as an anticoagulant and is administered intra-arterially. It is provided in a pharmaceutical form coded as PHF00231MIG, with a maximum daily dose of 2500 units and a total maximum dose of 910,000 units over 52 weeks.
**Oxaliplatin** is another antineoplastic antimetabolite administered intravenously. It is provided in the same pharmaceutical form as irinotecan, PHF00230MIG, with a maximum daily dose of 85 mg/m² and a total maximum dose of 2210 mg/m² over the treatment period.
**Capecitabine** is administered orally in a pharmaceutical form coded as PHF00009MIG. The maximum daily dose is 2000 mg/m², with a total maximum dose of 485,333 mg/m² over 52 weeks. It is also classified as an antineoplastic antimetabolite.
**Floxuridine** is provided as a powder for injection and is administered intra-arterially. The maximum daily dose is 0.12 mg/kg, with a total maximum dose of 43.68 mg/kg over the treatment period. It is classified as an antineoplastic antimetabolite.
**Bevacizumab** is a monoclonal antibody administered intravenously in a pharmaceutical form coded as PHF00230MIG. The maximum daily dose is 5 mg/g, with a total maximum dose of 130 mg/kg over 52 weeks.
**Fluorouracil** is administered either as an intravenous bolus injection or via IV infusion. It is provided in a pharmaceutical form coded as PHF00231MIG, with a maximum daily dose of 1200 mg/m² and a total maximum dose of 728,000 mg/m² over the treatment period. It is classified as an antineoplastic antimetabolite.
**Calcium folinate** is administered intravenously in a pharmaceutical form coded as PHF00190MIG. The maximum daily dose is 400 mg/m², with a total maximum dose of 10,400 mg/m² over 52 weeks. It serves as a detoxificantia for oncolytics.
**Dexamethasone acetate** is administered intra-arterially in a pharmaceutical form coded as PHF00245MIG. The maximum daily dose is 1.8 mg, with a total maximum dose of 650 mg over the treatment period. It is classified as a corticosteroid.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to evaluate the efficacy of these treatments in prolonging survival in patients with initially unresectable colorectal liver metastases.
Efficacy
Efficacy in this clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is **Overall Survival (OS)**, which will be measured to determine the effectiveness of the treatment in prolonging life in patients with initially unresectable colorectal liver metastases. Secondary endpoints include **Progression-free Survival (PFS)**, **Hepatic Progression-free Survival (hPFS)**, **Conversion to resection rate**, **Objective response rate (ORR)**, **Disease Control Rate (DCR)**, **Pathological response rate**, **Surgical complication rate** (classified by Clavien Dindo), **Adverse events and toxicity** (graded ≥ 3 according to the Common Terminology Criteria for Adverse Events, version 5.0), **Quality of Life (QoL)**, and **Costs per quality adjusted life years (QALYs)**.
The trial will involve the administration of various medicinal products, including **IRINOTECAN HYDROCHLORIDE**, **HEPARIN**, **OXALIPLATIN**, **CAPECITABINE**, **FLOXURIDINE**, **BEVACIZUMAB**, **FLUOROURACIL**, **CALCIUM FOLINATE**, and **DEXAMETHASONE ACETATE**. These products will be administered through different routes such as intravenous, intraarterial, and oral, depending on the specific product. The maximum treatment period for each product is 52 weeks.
Data collection for efficacy assessment will be conducted at specified intervals throughout the trial, with the final analysis occurring at the end of the treatment period. The trial is designed to compare the efficacy of hepatic arterial infusion pump chemotherapy combined with systemic therapy versus systemic therapy alone. The trial is expected to start recruitment in June 2024 and is estimated to conclude in December 2034.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18 years ≤ 75 years
- Histologically confirmed colorectal adenocarcinoma.
- Unresectable synchronous colorectal liver metastases according to a Liver Expert Panel (CT-scan obtained ≤ 4 weeks prior to registration for screening), defined as: o CRLM that are potentially resectable or locally treatable with two-stage approach, with resection and/or ablation or after portal vein embolization AND for which starting with systemic therapy is preferred because of the number, size, location or distribution of the metastases. o CRLM that are technically untreatable with local therapies without first downsizing
- No extrahepatic metastases. Patients with small (≤ 10 mm) extrahepatic lesions that are not clearly suspicious of metastases are eligible.
- No previous systemic therapy for colorectal cancer.
- Positioning of a catheter for HAIP chemotherapy is technically feasible based on imaging. The default site for the catheter insertion is the gastroduodenal artery (GDA). Accessory or aberrant hepatic arteries are no contraindication for catheter implantation. The GDA should have at least one branch to the liver. Accessory or aberrant hepatic arteries should be ligated to allow for cross perfusion to the entire liver through intrahepatic shunts. Not eligible: o Patients with significant (>50%) celiac trunk or superior mesenteric artery (SMA) stenosis o Patients with any celiac trunk stenosis and a replaced or accessory hepatic artery o Patients with both a replaced right and replaced left hepatic artery. A CT arterial phase is mandatory before randomisation in case of any celiac trunk or SMA stenosis. The sponsor study team is consulted in case of doubt about technical feasibility.
- ECOG performance status 0 or 1.
- Life expectancy of at least 12 weeks.
- Known mutation status of RAS and BRAFV600E.
- Primary tumour in situ and resectable without neoadjuvant therapy.
- Patient is eligible for surgery, as assessed by the treating surgeon
- Patient is eligible for at least doublet chemotherapy, as assessed by the treating oncologist.
- Laboratory requirements: i.e. adequate bone marrow, liver and renal function (obtained within 15 days prior to registration for screening). o Hb ≥ 5.5 mmol/L o absolute neutrophil count (ANC) ≥1.5 x 109/L o platelets ≥100 x 109/L o total bilirubin ≤ 1.5 times the upper limit of normal (ULN) o ASAT/AST ≤ 5 x ULN o ALAT/ALT ≤ 5 x ULN o alkaline phosphatase ≤ 5 x ULN o Serum creatinine ≤ 1.5 x upper limit of normal or a MDRD (eGFR) ≥ 45 ml/min; o Prothrombin time or INR < 1.5 x ULN (> 1.5 x ULN accepted for patients treated with coumarin derivates. These patients will be treated with LMWH or DOAC instead)
- Before registration, written informed consent must be given and signed according to ICH/GCP, and national/local regulations.
Exclusion Criteria
- Prior hepatic radiation, resection, or ablation.
- Serious non-healing wound, ulcer, or bone fracture.
- Chronic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone equivalent excluding inhaled steroids).
- Known serious infections (uncontrolled or requiring treatment).
- History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for HAIP-SYST or standard systemic therapy.
- Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
- Underlying liver disease including liver fibrosis and cirrhosis
- Any comorbidity or condition that interferes with the planned study treatment or the prognosis of CRLM, determined by the treating physician.
- Prior or concurrent second malignancy other than the disease under study or one whose natural history or treatment is likely to interfere with any study endpoints of safety or the efficacy of the study treatment(s) as discussed in the local MDT. The following malignancies are allowed: (a) malignancy treated with curative intent and with no evidence of active disease present within 3 years prior to inclusion (b) adequately controlled nonmelanomatous skin cancer (c) adequately treated carcinoma in situ without current evidence of disease Prior or concurrent second malignancies other than (a), (b) and (c) must be reviewed and agreed to with the sponsor study team.
- Obstructive primary tumour requiring emergency surgery, primary tumour necessitating a multivisceral resection/abdominoperineal resection or an intermediate (N+) or locally advanced rectal tumour (defined as a tumour with at least one of the following characteristics: tumour >5 cm; mesorectal fascia (MRF) ingrowth or ingrowth in adjacent organ on MRI (T4); Nodal positive primary tumour, i.e. at least one lymph node >8 mm or 4 lymph nodes >5 mm on CT scan or MRI.)
- MMR deficiency.
- DPD-deficiency.
- Pregnant or lactating women.
- Serious concomitant systemic disorders that would compromise the safety of the patient or his/her ability to complete the study, at the discretion of the investigator.
- Organ allografts requiring immunosuppressive therapy.
- History of clinically significant cardiovascular disease including, but not limited to, the following: New York Heart Association Heart Failure Class 2 or greater (Appendix G), major cardiovascular events or interventions within 6 months prior to registration for screening (e.g. myocardial infarction, endarterectomy) randomisation, unstable arrhythmias or unstable angina.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 The Netherlands | Recruiting | 10 Jun 2024 | — |
| Netherlands | — | — | 306 |
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 |
|---|---|---|---|---|---|---|
CALCIUM FOLINATE | Other | PHF00190MIG | INTRAVENOUS | 400 | 52 | SCP132603 |
OXALIPLATIN | Other | PHF00230MIG | INTRAVENOUS | 85 | 52 | SCP128961 |
BEVACIZUMAB | Other | PHF00230MIG | INTRAVENOUS | 5 | 52 | SCP29096188 |
IRINOTECAN | Other | PHF00230MIG | INTRAVENOUS | 180 | 52 | SCP160940 |
HEPARIN | Other | PHF00231MIG | INTRAARTERIAL USE | 2500 | 52 | SCP136436 |
CAPECITABINE | Other | PHF00009MIG | ORAL | 2000 | 52 | SCP131876 |
DEXAMETHASONE | Other | PHF00245MIG | INTRAARTERIAL USE | 1.8 | 52 | SCP10332310 |
FLUOROURACIL | Other | PHF00231MIG | INTRAVENOUS BOLUS INJECTION/IV INFUSION | 1200 | 52 | SCP1165178 |