| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with liver-only non resectable colorectal metastases. |
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| E.1.1.1 | Medical condition in easily understood language |
| Liver cancer with colorectal metastases. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the efficacy of CT intensification combining HAI oxaliplatin plus IV FOLFIRI plus targeted therapy (i.e. anti-EGFR or bevacizumab) to conventional systemic CT alone plus targeted therapy (i.e. 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). |
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| E.2.2 | Secondary objectives of the trial |
Efficacy, comparison between the two arms of :
• Progression-free survival (PFS, overall, hepatic, and extrahepatic)
• Overall survival (OS)
• Objective response rate (ORR)
• Depth of response (DoR)
Tolerance, comparison between the two arms of :
• Toxicity (NCI-CTCAE v4.0)
Feasibility :
• Proportion of patients receiving ≥ 4 cycles of HAI oxaliplatin (experimental arm only), dose-intensity of oxaliplatin and other systemic cytotoxic/targeted agents
• Description of the treatment received in each arm
• Description and frequency of HAI catheter-related complications (experimental arm only): dissection or thrombosis of hepatic artery, infection, bleeding, extrahepatic perfusion, incomplete hepatic perfusion, occlusion of catheter not responding to fibrinolysis, migration of the catheter tip. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
EXPLORATORY AND ANCILLARY STUDY OBJECTIVES
• Duration of response
• Early tumor shrinkage (ETS)
• Complete pathological response in case of CRLM resection.
• For the patients with curative surgery, time without any chemotherapy in the two arms in the period between R0/R1 surgery and new chemotherapy for recurrence or date of last follow-up in the absence of recurrence.
• Quality of life (QLQ-C30 and QLQ-LMC21)
• Prognostic value of circulating free tumor DNA |
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| E.3 | Principal inclusion criteria |
1.Histologically confirmed colorectal cancer (CRC), and radiologic or histologic proof of CRLM
not amenable to a curative intent-treatment after two months to 6 months of first-line induction CT
2.First-line CT with oxaliplatin and/or irinotecan combined with a fluoropyrimidine and a targeted therapy (e.g., anti-EGFR or antiangiogenic antibody) for metastatic disease (patients ending their adjuvant chemotherapy after primary tumor resection since less than 6 months should also have received first-line chemotherapy for metastatic disease)
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 criteria) or doubling of serum levels of carcinoembryonic antigen (CEA) or 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.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.Adequate contraception if applicable
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| E.4 | Principal exclusion criteria |
NON-INCLUSION 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. 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)
3. Patient with contraindication for trial drugs (investigators have to refer to drugs SmPC, see appendix 1); contraindication limited to targeted therapy (e.g., anti-EGFR or antiangiogenic antibody) is not an exclusion criteria
4. Sensory neuropathy ≥ grade 2 (NCI-CTAE v.4.0)
5. Significant chronic liver disease (resulting in portal hypertension and/or liver insufficiency)
6. Allergy to contrast media that cannot be managed with standard care
7. Previous organ transplantation, HIV or other immunodeficiency syndromes
8. 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
9. 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, symptomatic congestive heart failure, uncontrolled hypertension…)
10. Ionic disorders as:
• Kalemia ≤ 1 x ULN
• Magnesemia < 0.5 mmol/L
• Calcemia < 2 mmol/L
11. Patient with known dihydropyrimidine dehydrogenase deficiency
12. QT/QTc > 450 msec for men and > 470 msec for women
13. Concomitant intake of St. John's wort
14. Patient already included in another clinical trial with an experimental treatment
15. Pregnancy or lactation
16. Patients deprived of liberty or under guardianship
17. Patients unable to undergo medical monitoring test for geographical, social or psychological reasons
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Curative-intent (R0-R1) resection (and/or ablation) rate (CRR) of CRLM confirmed by a systematic review of the surgical and pathological report by an independent committee blind to the treatment received |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
- Efficacy:
• PFS (overall, hepatic and extrahepatic): PFS is defined by the delay between randomization and the occurrence of a progression or death, or the date of last follow-up in patients alive without progression. For hepatic PFS, only hepatic progressions are taken into account, patients with extra-hepatic progression are censored at the time of this progression; for extra-hepatic PFS, only extra-hepatic progressions are taken into account, patients with hepatic progression are censored at the time of this progression.
• OS: defined by the delay between randomization and the occurrence of death due to any cause, or the date of last follow-up in patients alive.
• ORR (best overall response according to RECIST v1.1, appendix 2) evaluated by CT scan/MRI every 8 weeks.
• DoR: relative change in the sum of longest diameters of RECIST target lesions at the nadir, in the absence of new lesions or progression of non-target lesions, as compared to baseline.
- Feasibility/Tolerance
• Feasibility of HAI oxaliplatin plus IV FOLFIRI (plus anti-EGFR or antiangiogenic antibody). Feasibility will be assessed by the proportion of patients receiving at least 4 cycles of chemotherapy with oxaliplatin (by HAI only in the HIA arm).
• Treatment received: number of cycles/injection of each drug will be described as well as the corresponding dose.
• Tolerance of HAI oxaliplatin plus IV FOLFIRI (plus anti-EGFR or antiangiogenic antibody) as compared with systemic chemotherapy iv alone plus target therapy (patients will be evaluated for toxicity every 14 days). Safety will be assessed by the toxicity grading of the National Cancer Institute (NCI-CTCAE version 4.0, appendix 3). To be considered evaluable for safety, patients must have received at least one cycle or a treatment dose.
• Type and frequency of complications related to the HAI catheter will be described and registered as well as treatment related mortality.
- Exploratory/ancillary endpoints
• Duration of objectives and stable responses.
• ETS: relative change in the sum of longest diameters of RECIST target lesions at week 8 compared to baseline.
• Complete pathological response in case of CRLM resection.
• For the patients with curative surgery, time without any chemotherapy in the two arms in the period between R0/R1 surgery and new chemotherapy for recurrence or date of last follow-up in the absence of recurrence.
• Quality of life (QL) assessed by the European Organization for Research and Treatment of Cancer (EORTC) core QL questionnaire, the EORTC QLQ-C30 and QLQ-LMC21 (Liver colorectal metastasis Module) (appendix 4).
• To assess the prognostic value of free tumor DNA.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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