Improving SUrgery of Liver Metastases: a Trial of the Arterial Chemotherapy Network

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

20 participants

Study Classification

INTERVENTIONAL

Study Start Date

2018-07-25

Study Completion Date

2021-11-15

Brief Summary

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National trial, multicenter, randomized, phase II comparing treatment intensification with hepatic arterial infusion chemotherapy plus systemic chemotherapy (CT) to systemic chemotherapy alone in patients with liver-only colorectal metastases (CRLM) considered still non resectable after at least two months of systemic induction chemotherapy.

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Detailed Description

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to compare the efficacy of CT intensification combining hepatic arterial infusion(HAI) oxaliplatin plus IV FOLFIRI plus targeted therapy (anti-epidermal growth factor receptor (EGFR) or bevacizumab) to conventional systemic CT alone plus targeted therapy (anti-EGFR or antiangiogenic antibody), in patients with liver-only CRLM not amenable to curative-intent resection (and/or ablation) after systemic induction CT in terms of conversion to complete (R0 R1) resection (or ablation) rate (CRR).

Conditions

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Colorectal Cancer Metastatic

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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HAI oxaliplatin combined with I.V. FOLFIRI + target therapy

* HAI oxaliplatin 100 mg/m² on D1
* I.V. cetuximab 500 mg/m² or panitumumab 6 mg/kg or bevacizumab 5 mg/kg D1 according to RAS status and prior response/tolerance to systemic induction CT
* modified FOLFIRI regimen without fluorouracil bolus
* I.V. irinotecan 180 mg/m² D1
* I.V. bolus 5-Fluorouracil (5-FU): 0
* I.V. leucovorin 400 mg/m² in 2 hours D1
* I.V. continuous infusion 5-FU 2400 mg/m² in 46 hours

Group Type EXPERIMENTAL

Oxaliplatin, Cetuximab, Bevacizumab, Panitumumab, Irinotecan, Leucovorin, 5-Fluorouracil

Intervention Type DRUG

Oxaliplatin 100 mg/m² infusion in 2 hours, Cetuximab 500mg/m² infusion in 2 hours, Bevacizumab 5 mg/kg infusion in 30 minutes, Panitumumab 6 mg/kg, Irinotecan 180 mg/m² over 90 minutes to begin 30 minutes after folinic acid infusion is started, Leucovorin 400 mg/m² infusion in 2 hours, 5-Fluorouracil 2400 mg/m² infusion continuous in 46h

conventional systemic CT

* Response to systemic induction CT
* Toxicity and duration of the systemic induction CT
* RAS status
* Current guidelines/standard of care

Group Type ACTIVE_COMPARATOR

Oxaliplatin, Cetuximab, Bevacizumab, Panitumumab, Irinotecan, Leucovorin, 5-Fluorouracil

Intervention Type DRUG

Oxaliplatin 100 mg/m² infusion in 2 hours, Cetuximab 500mg/m² infusion in 2 hours, Bevacizumab 5 mg/kg infusion in 30 minutes, Panitumumab 6 mg/kg, Irinotecan 180 mg/m² over 90 minutes to begin 30 minutes after folinic acid infusion is started, Leucovorin 400 mg/m² infusion in 2 hours, 5-Fluorouracil 2400 mg/m² infusion continuous in 46h

Interventions

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Oxaliplatin, Cetuximab, Bevacizumab, Panitumumab, Irinotecan, Leucovorin, 5-Fluorouracil

Oxaliplatin 100 mg/m² infusion in 2 hours, Cetuximab 500mg/m² infusion in 2 hours, Bevacizumab 5 mg/kg infusion in 30 minutes, Panitumumab 6 mg/kg, Irinotecan 180 mg/m² over 90 minutes to begin 30 minutes after folinic acid infusion is started, Leucovorin 400 mg/m² infusion in 2 hours, 5-Fluorouracil 2400 mg/m² infusion continuous in 46h

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

1. Histologically confirmed colorectal cancer (CRC), and radiologic or histologic proof of CRLM not amenable to a curative intent-treatment.
2. At least two months of prior induction systemic CT with oxaliplatin and/or irinotecan combined with a fluoropyrimidine combined or not to a targeted therapy (e.g., anti-EGFR or antiangiogenic antibody) for metastatic disease (patients ending their adjuvant chemotherapy after primary tumor resection since more than 6 months should also have received first-line chemotherapy for metastatic disease). Further systemic chemotherapy lines are allowed.
3. Unresectability of the CRLM will be confirmed by a centralized multidisciplinary expert panel (composed of surgeons, radiologists, interventional radiologists and medical oncologists). The panel will review the CT scan and MRI of the patients (weekly web conference). Non-resectability criteria (one of the following criteria):

* Upfront R0/R1 resection of all CRLM (that leaves at least two adequately perfused and drained segments) is not possible
* and/or metastases in contact with major vessels of the remnant liver which would require resection of the vessel for an R0 resection (i.e., tumor involvement of main portal right and left portal veins, of the three main hepatic veins, or of the retrohepatic vena cava)
* and/or documented progressive disease on imaging (according to the RECIST v1.1) or doubling of serum levels of carcinoembryonic antigen (CEA) or carbohydrate antigen 19-9 (CA 19-9) following ≥2 months of induction CT
4. At least one measurable liver metastasis according to the RECIST v1.1
5. Age ≥18 years
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
7. Normal liver function, i.e. bilirubin \<1.5 times the upper limit of normal values (ULN), aminotransferases \<5 ULN, alkaline phosphatase \<5 ULN
8. International normalized ratio (INR) \<1.5 ULN
9. Neutrophils \>1500/mm³, platelets \>100 000/mm³, hemoglobin \>9 g/dL (transfusion allowed)
10. Calculated creatinine clearance \>50 mL/min (Cockcroft and Gault formula)
11. Informed consent signed by the patient or his/her legal representative
12. Patient affiliated to a social security regimen
13. Potentially reproductive patients must agree to use an effective contraceptive method or practice adequate methods of birth control or practice complete abstinence while on treatment, and for at least 6 months after the last dose of study drug.
14. Uracilemia \<16 ng/ml

* Proteinuria \>1 g,
* Gastro-intestinal fistulae or perforation,
* Hypersensitivity to Chinese hamster ovary cell products or other human recombinant antibody,
* Major surgery in the last 28 days.

* Interstitial lung disease,
* Pulmonary fibrosis.
9. Significant chronic liver disease (resulting in portal hypertension and/or liver insufficiency)
10. Allergy to contrast media that cannot be managed with standard care
11. Previous organ transplantation, HIV or other immunodeficiency syndromes
12. Concomitant or past history of cancer within 5 years prior to entry into the trial other than adequately treated basal-cell skin cancer or in situ carcinoma of the cervix
13. Patients with clinically significant active heart disease or myocardial infarction in the last 6 months
14. Concomitant medications/comorbidities that may prevent the patient from receiving study treatments as uncontrolled intercurrent illness (for instance: active infection, active inflammatory disorders, inflammatory bowel disease, intestinal obstruction, uncontrolled hypertension systolic \>15 and diastolic \>9, symptomatic congestive heart failure…)
15. Ionic disorders as:

* Kalemia ≥1 x ULN
* Magnesemia \<0.5 mmol/L
* Calcemia \<2 mmol/L
16. Patient with a dihydropyrimidine dehydrogenase (DPD) deficiency; Uracilemia ≥16 ng/ml, the test should be done for all patients before first 5-FU administration, according to "agence nationale de sécurité du médicament" (ANSM) communication regarding recommendation about high risk of no testing DPD in patient before 5-FU administration
17. QT/QTc \>450 msec for men and \> 470 msec for women
18. Concomitant intake of St. John's wort
19. Patient already included in another clinical trial with an experimental treatment
20. Pregnancy or lactation
21. Patients deprived of liberty or under guardianship
22. Patients unable to undergo medical monitoring test for geographical, social or psychological reasons

Exclusion Criteria

1. Patient eligible for curative-intent treatment of CRLM (i.e. resection and/or thermoablation), according to the local multidisciplinary team and/or the central review.
2. Definitive anatomical contraindication to complete surgical resection (any of the following criteria):

* More than two lesions in all liver segments
* Bilobar liver metastasis and more than three lesions \>3 cm in the hepatic lobe the least affected (i.e. the future remnant liver)
* Bilobar liver metastasis and disease liver extend \>50%
3. Extrahepatic tumor disease (except ≤3 lung nodules \<10 mm deemed amenable to curative-intent resection/thermoablation and non-resected primary tumor with no or mild symptoms)
5. Disease progression after FOLFOXIRI/FOLFIRINOX
6. Sensory neuropathy ≥ grade 2 (National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4.0)

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No