Clinical trial NCT06332079: Holmium-166 TARE in Liver Limited Unresectable Colorectal Cancer Patients
Official title: Phase II Study Evaluating Holmium-166 TARE Followed by Maintenance Therapy in Liver Limited Unresectable Colorectal Cancer Patients After First-line Chemotherapy and Target Agents
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Colorectal Cancer Metastatic
Keywords: HOLMIUM
TARE
Maintenance therapy
Liver-limited colorectal cancer
Unresectable colorectal cancer
Lead sponsor: Gruppo Oncologico del Nord-Ovest
Sponsor class: OTHER
First posted: 2024-03-27
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Two cohorts of patients will be included according to the two main prognostic populations in mCRC (left sided, RAS/BRAF wild-type and, right-sided and/or RAS mutated tumors) treated with different maintenance therapy (fluoropyrimidine plus anti-EGFR or bevacizumab).

A total of 23 patients will be enrolled in each cohort.
Primary purpose: TREATMENT

Brief summary: The aim of this study is to assess the efficacy of 166Ho-TARE followed by maintenance therapy with fluoropyrimidine and anti-EGFR or bevacizumab in liver-limited unresectable colorectal cancer patients, in terms of progression free rate 9- and 8-months for cohort A and B, respectively.

Detailed description: HAITI is a phase II, single-arm trial of 166Ho-TARE followed by maintenance therapy in liver-limited unresectable colorectal cancer patients, achieving partial response or stable disease according to RECIST 1.1 criteria after 6-12 cycles of induction first-line chemotherapy.

Two cohorts of patients are included:

* left sided RAS/BRAF wild-type (cohort A)
* right-sided and/or RAS mutated (cohort B)

Enrolled patients will be treated with different maintenance therapy according to study cohort (fluoropyrimidine + anti-EGFR or bevacizumab).

Eligibility criteria: Inclusion Criteria:

* Written informed consent to study procedures;
* Age ≥18 years;
* 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;
* Life expectancy of at least 12 weeks;
* Hematopoietic function: absolute neutrophil count ≥ 1,500/mm3; platelet count

  ≥100,000/mm3; haemoglobin level ≥ 9 g/dL;
* Liver function: total bilirubin ≤ 1.5 times upper limit of normal (ULN); alkaline phosphatase

  ≤ 5 times ULN; AST ≤ 5 times ULN;
* Renal function: creatinine clearance \> 50 mL/min or serum creatinine 1.5 x UNL; no renal disease that would preclude study treatment or follow-up;
* Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient;
* Subjects and their partners must be willing to avoid pregnancy during the trial. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as outlined in Section 7.5 - Contraception, starting during study screening visit throughout the study period up to 180 days after the last dose of chemotherapy Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject;
* Will and ability to comply with the protocol

Inclusion criteria for 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.

Inclusion criteria for 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.

Exclusion Criteria:

* Patients with radiological evidence of extra liver distant metastases.
* Evidence of ascites, cirrhosis, portal hypertension, main portal venous tumour involvement or thrombosis, or any other contraindications to radioembolization treatment;
* Previous radiotherapy delivered to the liver;
* Patients with BRAF mutated and/or MSI-high tumours;
* Previous history of malignancy within the last 5 years will be excluded with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ;
* Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer);
* Active uncontrolled infections or other clinically relevant concomitant illness contraindicating study procedures and treatment administration Clinically significant (e.g. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF), serious cardiac arrhythmia requiring medication
* Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study and until 180 days after the last trial treatment;
* History of a previous allergic reaction to contrast media that would preclude safe angiography of the hepatic arteries, in the opinion of the treating Interventional Radiologist;
* Known hypersensitivity to fluoropyrimidine, anti-VEGF or anti-EGFR MoAb.
* Psychiatric or addictive disorders, or other conditions that, in the opinion of the investigator, would preclude study participation;
* Withdrawal of the consent to take part to the study

Primary outcomes:
measure: Progression-free survival (PFS) Rate
timeFrame: 36 months
Secondary outcomes:
measure: Overall Toxicity rate
timeFrame: 36 months
measure: Grade 3/ Grade 4 Toxicity rate
timeFrame: 36 months
measure: Post-treatment Disease Control Rate (DCR)
timeFrame: 36 months
measure: Progression free survival
timeFrame: 36 months
measure: Overall Survival
timeFrame: 36 months
measure: Dose-response relationships
timeFrame: 36 months
measure: Quality of Life (QoL) assessed using the EORTC QLQ-CR29 questionnaire
timeFrame: 36 months
measure: Quality of Life (QoL) assessed using the EORTC QLQ-CR30 questionnaire
timeFrame: 36 months
measure: Quality of Life (QoL) assessed using the EuroQol EQ-5D questionnaire
timeFrame: 36 months
Other outcomes:
Locations:
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana
Study officials:
affiliation: Azienda Ospedaliero, Universitaria Pisana
name: Gianluca Masi, MD
role: PRINCIPAL_INVESTIGATOR
References: