Induction Treatment for Initially Unresectable Colorectal Liver Metastases: Combined Hepatic Arterial Infusion Pump Therapy with Systemic Therapy (PUMP-IT RCT)

Netherlands Cancer Institute (NKI)

Status and phase: Enrolling; Phase 3

Conditions: Vascular Access Device; Liver Metastases; Floxuridine; Colorectal Neoplasms

Treatments: Drug: Intra arterial infusion Floxuridine (FUDR) combined with systemic therapy; Device: Hepatic arterial infusion pump (HAIP); Drug: Systemic therapy (standard of care)

Study type: Interventional

Funder types: Other

Identifiers

NCT06857773

M23PIT

2023-506194-35-00 (EU Trial (CTIS) Number)

Details and patient eligibility

About

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

Enrollment: 306 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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306 participants in 2 patient groups

A: systemic therapy according to standard of care

Active Comparator group

Description:

Patients included in the control arm will receive systemic therapy according to standard of care

Treatment:

Drug: Systemic therapy (standard of care)

B: combined HAIP-therapy and systemic therapy

Experimental group

Description:

Patients included in the experimental arm undergo surgery for pump placement and resection of the primary tumor. Followed by combined induction treatment with floxuridine via the hepatic arterial infusion pump (1cycle is 4 weeks) and systemic therapy (FOLFOX or FOLFIRI, 1 cycle is 2 weeks)

Treatment:

Device: Hepatic arterial infusion pump (HAIP)

Drug: Intra arterial infusion Floxuridine (FUDR) combined with systemic therapy