Clinical trial NCT06857773: Induction Treatment for Initially Unresectable Colorectal Liver Metastases: Combined Hepatic Arterial Infusion Pump Therapy With Systemic Therapy
Official title: Hepatic Arterial Infusion PUMP Chemotherapy Combined With Systemic Therapy Versus Systemic Therapy Alone as Induction Therapy for Initially Unresectable Colorectal Liver Metastases: a Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Colorectal Neoplasms
Floxuridine
Liver Metastases
Vascular Access Device
Lead sponsor: The Netherlands Cancer Institute
Sponsor class: OTHER
First posted: 2025-03-04
Enrollment: 306
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of this randomized clinical trial is to investigate induction treatment with Hepatic Arterial Infusion Pump therapy combined with systemic therapy (HAIP-SYST) in chemotherapy-naive patients with unresectable colorectal liver metastases without extrahepatic disease. The main question it aims to answer is if combined HAIP-SYST improves survival compared to induction treatment with systemic therapy alone. Patients in the control arm will receive systemic therapy according to standard of care.

Study procedures experimental arm

* Surgery for pump placement and resection of the primary tumor
* Pre- and postoperative imaging (CT-anghiography, 99mTc-MAA scintigraphy)
* Induction treatment with hepatic arterial infusion pump therapy with Floxuridine combined with systemic therapy

Study procedures both arms

* Evaluation of resectability status by a National Liver Panel with surgeons and radiologists
* Questionnaires for Quality of Life


Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years.
* Histologically confirmed colorectal adenocarcinoma.
* Unresectable synchronous CRLM according to a National Liver Panel (CT-scan obtained ≤ 4 weeks prior to registration).
* 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 contra-indication 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. Patients with celiac trunk stenosis are not eligible. Patients with both a replaced right and replaced left hepatic artery are not eligible.
* 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.
* Patient is eligible for doublet chemotherapy.
* Laboratory requirements: i.e. adequate bone marrow, liver and renal function (obtained within 15 days prior to registration).

  * Hb ≥ 5.5 mmol/L
  * absolute neutrophil count (ANC) ≥1.5 x 109/L
  * platelets ≥100 x 109/L
  * total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
  * ASAT/AST ≤ 5 x ULN
  * ALAT/ALT ≤ 5 x ULN
  * alkaline phosphatase ≤ 5 x ULN
  * Serum creatinine ≤ 1.5 x upper limit of normal or a MDRD (eGFR) ≥ 45 ml/min;
  * Prothrombin time or INR \< 1.5 x ULN, unless coumarin derivates are used. All patients using coumarin derivates 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.
* Any malignancy, comorbidity or condition that interferes with the planned study treatment or the prognosis of CRLM, determined by the treating physician.
* History of prior malignancy except for the following: (a) malignancy treated with curative intent and with no evidence of active disease present within 3 years prior to inclusion, (b) curatively treated malignancies felt to be at low risk for recurrence by treating physician and MDT, (c) adequately controlled nonmelanomatous skin cancer, (d) adequately treated carcinoma in situ without current evidence of disease.
* Obstructive primary tumour requiring emergency surgery, primary tumour necessitating a multivisceral resection/abdominoperineal resection or a rectal tumour requiring preoperative short-course radiotherapy or chemoradiotherapy for local tumour control.
* 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.
* 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

Primary outcomes:
measure: Overall survival
timeFrame: Up to five years after randomization
Secondary outcomes:
measure: Progression-free survival
timeFrame: Up to five years after randomization
measure: Hepatic progression-free survival
timeFrame: Up to five years after randomization
measure: Conversion to resection rate
timeFrame: if CRLM convert to resectable, often at 3-6 months after start induction treatment
measure: Complete local treatment rate
timeFrame: if CRLM convert to resectable, often at 3-6 months after start induction treatment
measure: Objective response rate (ORR)
timeFrame: During protocol treatment, up to 6 months of induction treatment
measure: Disease control rate (DCR)
timeFrame: During protocol treatment, up to 6 months of induction treatment
measure: Pathological response rate
timeFrame: Pathological assessment of conversion surgery after induction treatment
measure: Surgical complication rate
timeFrame: at 30 days an 90 days postoperatively
measure: Adverse events and toxicity of HAIP-SYST and systemic therapy
timeFrame: During protocol treatment
measure: Quality of Life (QoL)
timeFrame: Up to five years after randomization
measure: Cost-effectiveness
timeFrame: Up to five years after randomization
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek-Netherland Cancer Institute
Study officials:
References: