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Intra-arterial Hepatic Beads Loaded With Irinotecan With Concomitant Chemotherapy With FOLFOX in Patients With Colorectal Cancer With Unresectable Liver Metastases: a Phase II Multicenter Study

ABSTRACT: Treatment of patients with colorectal cancer having liver metastases is currently based on systemic chemotherapy. Triple therapy with 5FU, oxaliplatin and irinotecan intravenously was effective in terms of response and secondary resectability, however it is particularly toxic. Hepatic intra-arterial chemotherapy (HIA) has been the subject of several studies. It has shown good efficacy with oxaliplatin and FUDR. However, the procedure is difficult to set up and reserved for experienced centers. The objective of this protocol is to use a triple therapy based on 5FU and oxaliplatin associated to irinotecan which is administered by hepatic intra-arterial route, loaded onto microbeads (DEBIRI). Furthermore, the procedure for chemo-embolization DEBIRI is limited to 2 sessions, and therefore could be more easily generalized.

DISEASE(S): Neoplasm Metastasis,Colorectal Cancer With Non Resectable Hepatic Metastasis,Colorectal Neoplasms

PROVIDER: 2143760 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Background Hepatic metastases of colorectal cancer (MCC) is quite common and is a major source of morbidity and mortality. There has been evidence to show that hepatic arterial chemoembolisation using DC beads (drug eluting beads, 100-300μm) loaded with irinotecan (DEBIRI) showed improved overall survival when compared to systemic therapy (FOLFIRI), but being larger they have their limitations. New 70-150μm beads are recently available and currently there is limited data concerning its use. Safety of these beads have not been tested in local patients. Hypothesis / Aim To study the safety and pharmacokinetics of the smaller 70-150μm DEBIRI in a pilot study of 5 patients. The smaller 70-150μm beads will be able to deliver a more consistent and higher dose to tumoral tissue with a smaller systemic dose. Being smaller and less embolic, it will also be better tolerated. Patients will also be genotyped for their UGT1A1*28 and UGT1A1*6 polymorphism status as the latter genotypes are associated with decreased clearance of irinotecan and SN-38 in Asian patients. Methods Single centre, pilot study, prospectively recruiting 5 patients with unilobar disease, refractory to systemic chemotherapy The primary endpoints: 1. establish safety and toxicity profile of the irinotecan loaded DEBIRI beads 2. establish pharmacokinetics and systemic exposure of irinotecan and its active metabolite, SN-38. The secondary outcome measurements: 1. the incidence and severity of adverse events, liver function parameters and laboratory abnormalities; 2. response rate, 3. progression free survival 4. overall survival Clinical Significance This treatment modality has the advantage of directly delivering irinotecan to the liver metastases from colorectal cancer. This local mode of drug delivery may result in a higher intratumoral drug concentration and rapid tumour shrinkage leading to downstaging of the hepatic metastatic lesions. These therapeutic outcomes may also downstage patients to hepatic resection.

Project description:Interventions: The treatment proposed in this clinical investigation plan is to repeatedly administer intra-arterial chemotherapy to hepatic metastases from colorectal cancer when the blood flow to and from the liver has been isolated via balloon catheters. The objective of this study is to evaluate the tumour response, progression-free survival, morbidity and mortality of repeated and isolated intra-arterial hepatic infusion of oxaliplatin compared with the standard systemic chemotherapy (intravenous 5-FU + leucovorin + oxaliplatin [FOLFOX] or oral capecitabine with IV oxaliplatin [XELOX]). The treatment proposed in this study is based on the hypothesis that direct arterial infusion of chemotherapy to metastatic tumours of the liver whilst the blood flow to the organ is isolated could potentially yield benefits that cannot be achieved with existing treatment regimens. There are three treatment stages; implantation of a vascular access device (known as the AVAS), intra-arterial chemotherapy infusions, and explantation of the AVAS. Implantation: the participant is admitted to hospital and the AVAS is surgically implanted under general anaesthetic. The AVAS is an implantable large bore cannula with one end that can be anastomosed directly onto a peripheral vessel and the opposite end exiting the patient’s skin. The device can be opened to access the patient’s vasculature when required and closed when the device is not in use. In accordance with the manufacturer’s Instructions-For-Use (IFU), the AVAS will be implanted in the axillary artery (i.e. the upper pectoral area) or in the common femoral artery (upper thigh) by a trained vascular surgeon. The implantation procedure takes around 2 hours. After implantation, the participant is monitored overnight. Intra- Primary outcome(s): Response rate of tumours in liver as assessed via CT scans (RECIST criteria)[4 weeks after explantation of the AVAS] Study Design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Assignment: Single group;Type of endpoint: Safety/efficacy

Project description:Raltitrexed is a potent thymidylate synthase (TS) inhibitor. Conversely to 5-fluorouracil (5FU), raltitrexed can be administered safely in patients with cardiovascular disease, as well as in patients with dihydropyrimidine dehydrogenase deficit. Since raltitrexed is administered in 15-minutes infusion, complications related to continuous infusion can be avoided, and it becomes a potential good candidate for locoregional treatments as hepatic intra-arterial or intra-peritoneal infusion. Despite these potential benefits over 5FU, clinical trials failed in their temptation to replace the 5FU in colorectal cancer patients, mainly due to raltitrexed toxicity at 3mg/m2 every 3 weeks. Oxaliplatin has demonstrated a synergic effect when combined with TS inhibitors, and its association with raltitrexed was evaluated at 130mg/m2 of oxaliplatin and 3mg/m2 of raltitrexed, every 3 weeks. Actually, one of the first-line standard regimens in metastatic colorectal cancer patients is the biweekly FOLFOX (85mg/m2 of oxaliplatin, and infusional 5FU) plus bevacizumab regimen, since a significant progression-free survival (PFS) benefit was observed over FOLFOX plus placebo. Biweekly administration of raltitrexed at 2mg/m2 demonstrated a favorable toxicity profile even in patients aged >65 years. Besides, the association of raltitrexed, oxaliplatin and bevacizumab seems safe. Then, the investigators decided to perform a randomized pharmacokinetic comparative study between biweekly TOMOX (raltitrexed 2 mg/m2 and oxaliplatin 85mg/m2) and triweekly TOMOX (raltitrexed 3 mg/m2 and oxaliplatin 130mg/m2) regimens in metastatic colorectal cancer patients, in a "ping-pong" crossover strategy to reduce the intra-individual variability. Bevacizumab was allowed at the dose of 5mg/kg or 7.5mg/kg, in biweekly and triweekly schedules, respectively. The secondary end-points were, objective response rate evaluated by RECIST 1.1 criteria, PFS, overall survival (OS), toxicity, and the comparison of toxicity between two arms for the first 2 cycles.

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Intra-arterial Hepatic Beads Loaded With Irinotecan With Concomitant Chemotherapy With FOLFOX in Patients With Colorectal Cancer With Unresectable Liver Metastases: a Phase II Multicenter Study

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