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Colon

HAITI

Introduction

The standard treatment for patients with Colorectal Liver Metastases unsuitable for radical liver surgery, is based on maintenance therapy with fluoropyrimidine plus target agent previously used in the induction treatment phase.
The optimal use of systemic and local ablative treatments for unresectable metastatic ColoRectal Cancer (mCRC) patients after induction chemotherapy plus target agent remains a challenging issue.
Three randomized studies (SAKK41/06, AIO 0207 and CAIRO3) showed the superiority of fluoropyrimidine plus bevacizumab over bevacizumab alone or observation as maintenance therapy in mCRC who received combination chemotherapy plus bevacizumab as first-line treatment.
According to the results of MACRO2, VALENTINO and PANAMA trials, the use of 5-fluoruracil plus anti-EGFR monoclonal antibody demonstrated a superiority in terms of PFS over anti-EGFR or 5-fluorouracil alone, becoming the standard choice as maintenance therapy in mCRC patients who received combination chemotherapy plus anti-EGFR as first-line treatment.
In mCRC patients with liver limited disease 90Y-TARE plus chemotherapy showed to increase median time to tumour progression over chemotherapy alone according to a phase III study.
More recently, the FOXFIRE randomized studies (FOXFIRE, SIRFLOX and FOXFIREGlobal) which investigated the efficacy and safety of 90Y-TARE plus first-line chemotherapy for unresectable mCRC patients, failed to demonstrate an advantage in term of OS, while 90Y-TARE seemed to improve time to liver progression.
Recently, the randomized phase III EPOCH trial, showed the efficacy of 90Y TARE in terms of PFS and hepatic PFS when added to second line chemotherapy in mCRC patients, without safety concerns.
In the last years, phase I-II studies showed the safety and considerable DCR of 166Ho TARE in patients with chemorefractory liver tumors and in a cohort of mCRC patients, leading to the registration as medical device for radioembolization treatment of liver tumors.
On the basis of these considerations, we designed a phase II, single arm trial of 166HoTARE followed by maintenance therapy in unresectable liver-limited colorectal cancer patients after first-line chemotherapy, which include 2 cohort of patients according to the two main prognostic populations in mCRC (cohort A: left sided, RAS/BRAF wild-type and, cohort B right-sided and/or RAS mutated tumors) treated with different maintenance therapy (fluoropyrimidine plus anti-EGFR or bevacizumab).

Selection criteria

All patients:

– Histologically proven diagnosis of colorectal adenocarcinoma, with or without primary tumour in situ;
– Liver-only disease at radiological exams involving less than 50% of liver volume;
– Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2;
– Patients with partial response or stable disease according to RECIST 1.1 criteria deemed unresectable after 6-12 cycles of induction first-line
chemotherapy.

Cohort A

– RAS/BRAF wild-type and left sided primary tumor;
– First-line induction chemotherapy regimen permitted up to 6-12 cycles with: FOLFOX or FOLFIRI + anti-EGFR (cetuximab or panitumumab);
– Patients who interrupted anti-EGFR target therapy during induction phase due to toxicity or other reasons, candidate to maintenance with fluoropyridine alone therapy can be enrolled.

Cohort B

– RAS mutated and/or right-sided primary tumor;
– First-line induction chemotherapy regimen admitted up to 6-12 cycles with:
FOLFOX/FOLFIRI/XELOX + bevacizumab or FOLFOXIRI + bevacizumab;
– Patients who interrupted bevacizumab during induction phase due to toxicity or other reasons, candidate to maintenance with fluoropyridine alone therapy
can be enrolled.

Objectives

Primary objective

Cohort A
The primary objective of this cohort is to assess the efficacy of 166Ho-TARE followed by maintenance therapy with fluoropyrimidine and anti-EGFR in terms of progression free rate at 9 months.

Cohort B
The primary objective of this cohort is to assess the efficacy 166Ho-TARE followed by maintenance therapy with fluoropyrimidine and anti-VEGF in terms of progression free rate at 8 months.

Secondary objective

In both cohorts secondary objectives are to evaluate 166Ho TARE followed by maintenance therapy in terms of:
– Safety profile
– DCR according to RECIST 1.1 criteria
– Progression free survival (PFS)
– Overall survival (OS)
– Dose-response relationship between tumor absorbed doses on SPECT/CT and progression free rate, tumor response and OS
– Quality of life (QoL)
– Translational objective
To explore the prognostic role of circulating tumor DNA (ctDNA) in patients with unresectable liver limited colorectal cancer treated with 66Ho-TARE followed by maintenance therapy with fluoropyrimidine and target agents after first-line chemotherapy.

Participating centers